Systems and methods for long term transdermal administration

ABSTRACT

Devices, systems, compositions and methods for long term or prolonged transdermal administration of an active agent are provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Non-Provisional applicationSer. No. 15/396,252, filed Dec. 30, 2016, now allowed, which claims thebenefit of U.S. Provisional Application No. 62/273,288, filed Dec. 30,2015, and of U.S. Provisional Application No. 62/367,055, filed Jul. 26,2016, each of which is incorporated herein by reference in its entirety.

TECHNICAL FIELD

The subject matter described herein relates to a transdermal deliverysystem comprising a backing for improved long term administration. Thesubject matter described herein further relates to a transdermaldelivery system comprising at least one segmented layer for improvedlong term administration. The delivery system is suitable for prolongedadministration of an active or therapeutic agent with improved adhesionto the skin at an administration site.

BACKGROUND

Transdermal delivery systems have become more desirable as they have theadvantage of avoiding difficulties associated with gastrointestinalabsorption of an active agent (e.g. effect of gastrointestinal pH and/orenzyme activity on the active agent, drug-food interactions,gastrointestinal side effects, eliminates pulsed entry into systemcirculation, and avoid high first-pass effect through the liver).Transdermal delivery systems may also increase patient compliance due tothe ability for the patient to self-administer and avoids more invasivetreatments such as injections. Transdermal delivery may advantageouslyprovide controlled, constant delivery of the active agent, which mayresult in less fluctuation in circulating levels of the agent ascompared to oral delivery.

Long term administration of transdermal patches is challenging,especially for patches that use occlusive backings. Most transdermalpatches cannot remain adhered to the skin or other administration sitefor an extended period of time, e.g. at least or about 7 days. However,continuous contact of the patch with the patient's skin is necessary forproper drug delivery from the patch. The FDA lists problems associatedwith transdermal patches which includes the patch not flexing orconforming to the skin; the patch not sticking or the edges of the patchcurling after 24 hours (www.fda.gov). Disadhesion may alter or preventdelivery of the drug from the patch. Friction between the layers of thepatch and the administration site may also cause the patch to buckle,wrinkle, and/or fail by losing contact with the skin. To address theseproblems, transdermal patches that are approved for long term use are ofsmall size (e.g. less than 25 cm²) such as the Catapres® or Ortho Evra®patches or require an over-sized overlay to cover the patch. The use ofan overlay increases patch size and results in about a 1.5-2 or 2-3 foldincrease in the total patch area. Therefore, use of an overlay is onlypractical for relatively small patches (e.g. not more than about 40cm²). Many of the multi-day use patch manufacturers recommend usingmedical tape to secure the patch. For example, the patient instructionsfor the fentanyl Duragesic® patch recommends applying first aid tape atthe edges or use of adhesive dressings as a patch overlay to prevent theproblem of patches that do not stick to the skin properly (seewww.duragesic.com).

Another approach to long term transdermal patches is the use of arelatively breathable backing layer to increase wear time. Success withthese patches is limited as the increased breathability of the backinglayer reduces drug flux requiring an increase in total patch area.

Therefore, there exists a need for transdermal compositions, devices andmethods that address at least these shortcomings.

The foregoing examples of the related art and limitations relatedtherewith are intended to be illustrative and not exclusive. Otherlimitations of the related art will become apparent to those of skill inthe art upon a reading of the specification and a study of the drawings.

BRIEF SUMMARY

The following aspects and embodiments thereof described and illustratedbelow are meant to be exemplary and illustrative, not limiting in scope.

It is an object of the present invention to provide methods andcompositions to effect long term or prolonged transdermal delivery of anactive agent.

In embodiments, the transdermal patch comprises a first backing layer;an interfacing adhesive layer; a second backing layer comprised of aplurality of segments that are at least partially separated; an adhesiveactive agent layer comprising at least one active agent; and a releaseliner. In embodiments, the first backing layer is comprised of anelastic material. In embodiments, the second backing layer and theadhesive active agent layer together comprise a composite layer wherethe composite layer is comprised of a plurality of segments that are atleast partially separated. In some embodiments, the plurality ofsegments are at least partially connected. In embodiments, at least thefirst backing layer and the interfacing adhesive layers are laminated.In some embodiments, the layers of the composite layer are laminated. Inembodiments, the adhesive active agent layer is comprised of an adhesivematrix.

In embodiments, the first backing layer is comprised of an elasticpolymer film, a multi-directional elastic woven fabric, amulti-directional elastic nonwoven fabric, a stretchable polymer film, astretchable woven fabric, or a stretchable nonwoven fabric. Inembodiments, the polymer fabric or polymer film is comprised of one ormore polymers selected from polyesters, polyethylenes, polypropylenes,polyvinylchloride, polyethylene vinyl acetate or copolymers thereof, andpolyurethanes. In some embodiments, the first backing layer has athickness of about 0.2-50 mil.

In embodiments, the interfacing adhesive layer is comprised of one ormore polymers selected from selected from acrylates, acrylatecopolymers, polyisobutylene, silicone, polystyrene butyl rubber,polyethylene vinyl acetate and copolymers thereof, and plasticizedpolymers. In embodiments, the interfacing adhesive layer comprises afirst adhesive layer adjacent the first backing layer and a secondadhesive layer adjacent the second backing layer.

In embodiments, the second backing layer is comprised of a materialselected from an occlusive material and a breathable material. Inembodiments, the second backing layer is comprised of one or morepolymers selected from polyesters, polyethylenes, polypropylenes,polystyrenes, polyvinylchloride, and a polyethyleneterephthalate/ethylene vinyl acetate laminate.

In embodiments, the composite layer further comprises a tie layerpositioned distal to the adhesive active agent layer. In embodiments,the tie layer is a rate-controlling membrane that controls the rate ofactive agent release.

In embodiments, the composite layer further comprises a contact adhesivelayer positioned between the adhesive active agent layer and the releaseliner. In some embodiments, each segment of the composite layer has asize of about 2-40 cm².

In embodiments, at least the first backing layer and the release linerare sized to extend about 0.5-1.0 cm beyond the perimeter of thecomposite adhesive layer.

In embodiments, the release liner is comprised of a material selectedfrom a silicone coated material, a fluorocarbon coated material, and afluorosilicone coated material.

In a further aspect, a method of transdermally administering an activeagent is provided. In embodiments, the method comprises removing arelease liner from the transdermal patch as described herein; andadhering the transdermal patch to the skin of a patient for a period upto about 10 days to deliver the active agent to said patient.

Additional embodiments of the present methods and compositions, and thelike, will be apparent from the following description, drawings,examples, and claims. As can be appreciated from the foregoing andfollowing description, each and every feature described herein, and eachand every combination of two or more of such features, is includedwithin the scope of the present disclosure provided that the featuresincluded in such a combination are not mutually inconsistent. Inaddition, any feature or combination of features may be specificallyexcluded from any embodiment of the present invention. Additionalaspects and advantages of the present invention are set forth in thefollowing description and claims, particularly when considered inconjunction with the accompanying examples and drawings.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an illustration of a transdermal patch having a compositebacking, an agent adhesive layer and a backing layer in accord withembodiments described herein.

FIG. 2 is an illustration of a transdermal patch comprising a layeredcomposite backing in accord with embodiments described herein.

FIG. 3 is an illustration of a composite backing in accord withembodiments described herein.

FIG. 4A is a top view illustration of a backing laminate layer. FIG. 4Bis a top view image of a divided backing layer.

FIG. 5 is a side view illustrating an exemplary composite backingcomprising separate pieces for a first or top layer.

FIGS. 6A-6C are illustrations of transdermal patches having a segmentedpatch layer in accord with embodiments described herein.

FIG. 7 is an illustration of a top-down view of the segmented patchlayer in accord with embodiments described herein.

FIG. 8 is an illustration of an exploded view of a transdermal patch inaccord with embodiments described herein.

FIG. 9 is an illustration of a bottom-up view of a segmented patch layerin accord with embodiments described herein.

DETAILED DESCRIPTION I. Definitions

Various aspects now will be described more fully hereinafter. Suchaspects may, however, be embodied in many different forms and should notbe construed as limited to the embodiments set forth herein; rather,these embodiments are provided so that this disclosure will be thoroughand complete, and will fully convey its scope to those skilled in theart.

It is to be understood that, unless otherwise indicated, these aspectsand embodiments are not limited to specific polymers, oligomers,crosslinking agents, additives, manufacturing processes, or adhesiveproducts. It is also to be understood that the terminology used hereinis for the purpose of describing particular embodiments only, and is notintended to be limiting.

Where a range of values is provided, it is intended that eachintervening value between the upper and lower limit of that range andany other stated or intervening value in that stated range isencompassed within the disclosure. For example, if a range of 1 μm to 8μm is stated, it is intended that 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μmare also explicitly disclosed, as well as the range of values greaterthan or equal to 1 μm and the range of values less than or equal to 8μm.

The singular forms “a,” “an,” and “the” include plural referents unlessthe context clearly dictates otherwise. Thus, for example, reference toa “polymer” includes a single polymer as well as two or more of the sameor different polymers, reference to an “excipient” includes a singleexcipient as well as two or more of the same or different excipients,and the like.

The use of terms of order or importance, including “first” and “second”,is to distinguish and identify individual elements and does not denoteor imply a particular order or importance unless clearly indicated bycontext.

The term “active agent” as used herein refers to a chemical material orcompound suitable for topical or transdermal administration and thatinduces a desired effect. The terms include agents that aretherapeutically effective, prophylactically effective, and cosmeticallyeffective agents. The terms “active agent”, “drug” and “therapeuticagent” are used interchangeably herein.

The term “hydrogel” is used in the conventional sense to refer towater-swellable polymeric matrices that can absorb a substantial amountof water to form elastic gels, wherein “matrices” are three-dimensionalnetworks of macromolecules held together by covalent or noncovalentcrosslinks. Upon placement in an aqueous environment, dry hydrogelsswell to the extent allowed by the degree of cross-linking.

The term “hydrogel composition” refers to a composition that eithercontains a hydrogel or is entirely composed of a hydrogel. As such,“hydrogel compositions” encompass not only hydrogels per se but alsocompositions that not only contain a hydrogel but also contain one ormore non-hydrogel components or compositions, e.g., hydrocolloids, whichcontain a hydrophilic component (which may contain or be a hydrogel)distributed in a hydrophobic phase.

“Matrix” as used herein refers to a solid or semi-solid substanceincluding, but not limited to, a polymeric material, adhesive or gel.The matrix typically serves as a repository or carrier for substancesincluding the therapeutic agent.

“Occlusive” as used herein refers to a material that limits thediffusion rate of moisture vapor and/or oxygen. A “non-occlusive”material allows a higher diffusion rate for moisture vapor and/oroxygen.

“Optional” or “optionally” means that the subsequently describedcircumstance may or may not occur, so that the description includesinstances where the circumstance occurs and instances where it does not.

The term “skin” as used herein refers to skin or other biologicalmembranes or mucosal tissue, including the interior surface of bodycavities that have a mucosal lining. The term “skin” should beinterpreted as including “mucosal tissue” and vice versa. It will beunderstood by persons of skill in the art that in most or all instancesthe same inventive principles apply to administration through otherbiological membranes such as those which line the interior of the mouth(e.g. oral mucosal membranes), gastro-intestinal tract, blood-brainbarrier, or other body tissues or organs or biological membranes whichare exposed or accessible during surgery or during procedures such aslaparoscopy or endoscopy.

“Substantially” or “essentially” means nearly totally or completely, forinstance, 90-95% or greater of some given quantity.

The term “therapeutically effective amount” as used herein refers to theamount of an active agent that is nontoxic but sufficient to provide thedesired therapeutic effect. The amount that is “effective” will varyfrom subject to subject, depending on the age and general condition ofthe individual, the particular active agent or agents, and the like asknown to those skilled in the art.

The terms “transdermal” or “transdermal delivery” as used herein referto administration of an active agent to a body surface of an individualso that the agent passes through the body surface, e.g., skin, and intothe individual's blood stream (systemic circulation). The term“transdermal” is intended to include transmucosal administration, i.e.,administration of a drug to the mucosal (e.g., sublingual, buccal,vaginal, rectal) surface of an individual so that the agent passesthrough the mucosal tissue and into the individual's blood stream.

The terms “transdermal patch”, “transdermal device” and/or “transdermalsystem” all relate to a layered patch, device or system that providestransdermal delivery of an active agent therefrom. The terms are usedinterchangeably herein.

II. Transdermal Devices and Systems

The systems and devices described herein are designed for prolonged orlong term transdermal administration of an active agent. Thecompositions may be used in devices, patches or systems suitable fortransdermal delivery of the active agent. Reference to a transdermaldevice, system or patch herein applies equally to each of the terms. Thedevices and systems are especially useful for long term delivery of theactive agent from the device. For the long term delivery, the systemmust remain adhered or substantially adhered to the administration siteas delivery of the active agent from the transdermal device requirescontact between the agent containing layer and the administration site(directly or indirectly). Most transdermal patches cannot or do notremain sufficiently adhered to the skin for an extended period of morethan a couple of days. Many commercial patches advise users to replacepatches that peel off the skin or become substantially unadhered. Theadhesion problem becomes greater for larger patch sizes and/or forpatches that are applied for longer durations such as more than 1-3days. Friction between moving skin and the static backing layerincreases shear resistance of the adhesive/drug layer that is adhered tothe stiff backing layer. These patches are either lifted off the skin orbecome buckled up from the skin, causing the patch to lose contact withthe skin. Eventually, this results in patch failure. This friction mayalso lead to skin irritation, particularly along the edges of the patch.The propensity for larger patches to buckle or fail practically limitsthe size of patches. Because the patch size is one factor in the dose ofthe active agent that is delivered, the patch size may also limit thedose and duration of administration of the active agent.

In some embodiments, the present transdermal devices and systems providea transdermal device or system that includes a composite backing layerthat reduces friction within the device or system and allows for longterm wear, larger patch size, and/or reduced skin irritation. In someembodiments, the present transdermal devices and systems provide atransdermal device or system that includes at least one layer that is atleast partially segmented or divided. In some embodiments, thetransdermal device or system includes at least one internal patch layerthat is at least partially segmented or divided, which reduces frictionwithin the device or system and allows for long term wear, larger patchsize, and/or reduced skin irritation.

In some embodiments, the transdermal device, patch or system is usefulfor long term or extended wear or administration. In embodiments, thetransdermal device is suitable for administration of at least about 3days or more. In some embodiments, the transdermal device is suitablefor administration of at least about or up to about 3-14 days. In someembodiments, the transdermal device is suitable for administration up toabout 10-14 days. In some embodiments, the transdermal device issuitable for administration of at least about or up to about 3-5 days,3-7 days, 3-10 days, 5-7 days, 5-10 days, 5-14 days, 6-10 days, 6-14days, 7-10 days, 7-14 days, 8-10 days, 8-14 days, 9-10 days, 9-14 days,or 10-14 days. In some non-limiting embodiments, the transdermal deviceis suitable for administration of at least about or up to about 3 days,4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, or 14 days. Bysuitable for administration, it is meant that the device, patch orsystem remains sufficiently adhered to the administration site to allowfor contact of the adhesive drug layer with the skin such that theactive agent is transdermally delivered. In embodiments, the device,patch or system is continuously adhered to the administration site. Insome embodiments, the device, patch or system is substantially adheredto the administration site.

FIG. 1 shows an embodiment of an exemplary transdermal patch, device orsystem, generally designated at 10, having a composite backing layer oroverlay. In this embodiment, the device includes a composite backinglayer 12, an adhesive drug layer 14 and an optional release liner 16.

The backing layer provides a structural element for holding orsupporting the adhesive drug layer. In the discussion of the backinglayer below, it will be appreciated that the discussion applies to thebacking layer as a whole as well as any one or more of the individuallayers of the composite backing layer. The backing layer may be formedof any suitable material as known in the art. In some embodiments, thebacking layer is occlusive or breathable. In some embodiments, thebacking layer is preferably impermeable or substantially impermeable tomoisture by preventing passage of all or substantially all moisture. Inone exemplary embodiment, the barrier layer has an MVTR (moisture vaportransmission rate) of less than about 50 g/m²/day. In some embodiments,the barrier layer has an MVTR of about 0.5-1500 g/m²/day or about 0.5-50g/m²/day. In some specific but not limiting embodiments, the barrierlayer has an MVTR of less than about or about 0.5 g/m²/day, 1 g/m²/day,5 g/m²/day, 10 g/m²/day, 15 g/m²/day, 20 g/m²/day, 25 g/m²/day, 30g/m²/day, 40 g/m²/day, or 50 g/m²/day. In some embodiments, the backinglayer is preferably inert and/or does not absorb components of theadhesive drug layer, including the active agent. In some embodiments,the backing layer preferably prevents release of components of theadhesive drug layer through the backing layer. The backing layer may beflexible, substantially flexible or nonflexible. The backing layer ispreferably at least partially flexible such that the backing layer isable to conform at least partially to the shape of the skin where thepatch is applied. In some embodiments, the backing layer is flexiblesuch that the backing layer conforms to the shape of the skin where thepatch is applied. In some embodiments, the backing layer is sufficientlyflexible to maintain contact at the application site with movement, e.g.skin movement. Typically, at least some of the materials used for thebacking layer should permit the device to follow the contours of theskin or other application site and be worn comfortably on areas of skinsuch as at joints or other points of flexure, that are normallysubjected to mechanical strain with little or no likelihood of thedevice disengaging from the skin due to differences in the flexibilityor resiliency of the skin and the device. In some embodiments, thebacking layer does not affect and/or control the release profile of theactive agent from the device. In some embodiments, the backing layer isnot the predominant factor affecting and/or controlling the releaseprofile of the active agent from the device.

In some embodiments, at least a portion of the transdermal patch has asize or surface area of about 5-200 cm². In some non-limitingembodiments, the transdermal patch has a size or surface area of about5-10 cm², 5-15 cm², 5-20 cm², 5-25 cm², 5-30 cm², 5-40 cm², 5-45 cm²,5-50 cm², 5-60 cm², 5-70 cm², 5-75 cm², 5-80 cm², 5-90 cm², 5-100 cm²,5-125 cm², 5-150 cm², 5-175 cm², 10-15 cm², 10-20 cm², 10-25 cm², 10-30cm², 10-40 cm², 10-45 cm², 10-50 cm², 10-60 cm², 10-70 cm², 10-75 cm²,10-80 cm², 10-90 cm², 10-100 cm², 10-125 cm², 10-150 cm², 10-175 cm²,10-200 cm², 15-20 cm², 15-25 cm², 15-30 cm², 15-40 cm², 15-45 cm², 15-50cm², 15-60 cm², 15-70 cm², 15-75 cm², 15-80 cm², 15-90 cm², 15-100 cm²,15-125 cm², 15-150 cm², 15-175 cm², 15-200 cm², 20-25 cm², 20-30 cm²,20-40 cm², 20-45 cm², 20-50 cm², 25-60 cm², 25-70 cm², 25-75 cm², 25-80cm², 25-90 cm², 25-100 cm², 25-125 cm², 25-150 cm², 25-175 cm², 25-200cm², 25-30 cm², 25-40 cm², 25-45 cm², 25-50 cm², 25-60 cm², 25-70 cm²,25-75 cm², 25-80 cm², 25-90 cm², 25-100 cm², 25-125 cm², 25-150 cm²,25-175 cm², 25-200 cm², 30-40 cm², 30-45 cm², 30-50 cm², 30-60 cm²,30-70 cm², 30-75 cm², 30-80 cm², 30-90 cm², 30-100 cm², 30-125 cm²,30-150 cm², 30-175 cm², 30-200 cm², 40-45 cm², 40-50 cm², 40-60 cm²,40-70 cm², 40-75 cm², 40-80 cm², 40-90 cm², 40-100 cm², 40-125 cm²,40-150 cm², 40-175 cm², 40-200 cm², 45-50 cm², 45-60 cm², 45-70 cm²,45-75 cm², 45-80 cm², 45-90 cm², 45-100 cm², 45-125 cm², 45-150 cm²,45-175 cm², 45-200 cm², 50-60 cm², 50-70 cm², 50-75 cm², 50-80 cm²,50-90 cm², 50-100 cm², 50-125 cm², 50-150 cm², 50-175 cm², 50-200 cm²,60-70 cm², 60-75 cm², 60-80 cm², 60-90 cm², 60-100 cm², 60-125 cm²,60-150 cm², 60-175 cm², 60-200 cm², 70-75 cm², 70-80 cm², 70-90 cm²,70-100 cm², 70-125 cm², 70-150 cm², 70-175 cm², 70-200 cm², 80-90 cm²,80-100 cm², 80-125 cm², 80-150 cm², 80-175 cm², 80-200 cm², 90-100 cm²,90-125 cm², 90-150 cm², 90-175 cm², 90-200 cm², 100-125 cm², 100-150cm², 100-175 cm², 100-200 cm², 125-150 cm², 125-175 cm², 125-200 cm²,150-175 cm², 150-200 cm², or 175-200 cm². In specific, but not limiting,embodiments, the transdermal patch has a size or surface area of about 5cm², 10 cm², 15 cm², 20 cm², 25 cm², 30 cm², 40 cm², 45 cm², 50 cm², 60cm², 70 cm², 75 cm², 80 cm², 90 cm², 100 cm², 125 cm², 150 cm², 175 cm²,or 200 cm². It will be appreciated that different layers of the backingand/or the device may have a different surface area or size. in oneembodiment, at least a portion (e.g. at least one layer) of the backingextends beyond the edge of at least the adhesive drug layer.

The transdermal patch may be prepared to have a thickness such that thedesired amount of drug formulation is contained within the patchincluding the desired components while maintaining a thickness that iswearable and comfortable for the subject. In some embodiments, thetransdermal patch has a thickness of about 2-200 mil including thecomposite backing layer and the adhesive drug layer. In specificnon-limiting embodiments, the transdermal patch has a thickness of about2-10 mil, 2-25 mil, 2-30 mil, 2-40 mil, 2-50 mil, 2-75 mil, 2-80 mil,2-100 mil, 2-125 mil, 2-150 mil, 2-175 mil, 2.5-10 mil, 2.5-25 mil,2.5-30 mil, 2.5-40 mil, 2.5-50 mil, 2.5-75 mil, 2.5-80 mil, 2.5-100 mil,2.5-125 mil, 2.5-150 mil, 2.5-175 mil, 2.5-200 mil, 3-10 mil, 3-25 mil,3-30 mil, 3-40 mil, 3-50 mil, 3-75 mil, 3-80 mil, 3-100 mil, 3-125 mil,3-150 mil, 3-175 mil, 3-200 mil, 5-10 mil, 5-25 mil, 5-30 mil, 5-40 mil,5-50 mil, 5-75 mil, 5-80 mil, 5-100 mil, 5-125 mil, 5-150 mil, 5-175mil, 5-200 mil, 7-10 mil, 7-25 mil, 7-30 mil, 7-40 mil, 7-50 mil, 7-75mil, 7-80 mil, 7-100 mil, 7-125 mil, 7-150 mil, 7-175 mil, 7-200 mil,8-10 mil, 8-25 mil, 8-30 mil, 8-40 mil, 8-50 mil, 8-75 mil, 8-80 mil,8-100 mil, 8-125 mil, 8-150 mil, 8-175 mil, 8-200 mil, 10-25 mil, 10-30mil, 10-40 mil, 10-50 mil, 10-75 mil, 10-80 mil, 10-100 mil, 10-125 mil,10-150 mil, 10-175 mil, 10-200 mil, 25-30 mil, 25-40 mil, 25-50 mil,25-75 mil, 25-80 mil, 25-100 mil, 25-125 mil, 25-150 mil, 25-175 mil,25-200 mil, 30-40 mil, 30-50 mil, 30-75 mil, 30-80 mil, 30-100 mil,30-125 mil, 30-150 mil, 30-175 mil, 30-200 mil, 40-50 mil, 40-75 mil,40-80 mil, 40-100 mil, 40-125 mil, 40-150 mil, 40-175 mil, 40-200 mil,50-75 mil, 50-80 mil, 50-100 mil, 50-125 mil, 50-150 mil, 50-175 mil,50-200 mil, 75-80 mil, 75-100 mil, 75-125 mil, 75-150 mil, 75-175 mil,75-200 mil, 80-100 mil, 80-125 mil, 80-150 mil, 80-175 mil, 80-200 mil,100-125 mil, 100-150 mil, 100-175 mil, 100-200 mil, 125-150 mil, 125-175mil, 125-200 mil, 150-175 mil, 150-200 mil, or 175-200 mil. In specific,but not limiting, embodiments, the transdermal patch has a thickness ofabout 2 mil, 2.5 mil, 3 mil, 4 mil, 5 mil, 7 mil, 7.5 mil, 8 mil, 10mil, 15 mil, 20 mil, 25 mil, 30 mil, 40 mil, 50 mil, 60 mil, 70 mil, 75mil, 80 mil, 90 mil, 100 mil, 125 mil, 150 mil, 175 mil, or 200 mil. Thethickness for the patch describes above may apply to the patch includingthe optional release liner or the patch as applied (including only thebacking and drug layers).

In a first aspect, as seen in FIGS. 2 and 3 , the backing layer oroverlay 12 is a composite comprising multiple or several layers to allowmovement within the composite backing/and or the adhesive drug layer 14.The composite layers may be laminated or otherwise adhered as known inthe art. Lamination generally refers to manufacture by layering andadhering materials. In embodiments as shown in FIG. 3 , the backinglayer comprises a first exterior or top layer 18, a second, middle layer20, and a third or bottom layer 22. In the embodiment as shown in FIG. 2, at least the second/middle layer 20 and the third/bottom layer 22 ofthe composite backing as well as the adhesive/drug layer 14,collectively indicated at 38, allow for shear yield and/or movement toallow dissipation of movement within the transdermal delivery system. Inother embodiments, at least the first/top layer 18 and the second/middlelayer 20 of the composite backing allow for shear yield and/or movementto allow dissipation of movement within the transdermal delivery system.

In non-limiting embodiments, the composite layer has a thickness ofabout 2-100 mil. In specific non-limiting embodiments, the compositelayer has a thickness of about 5-10 mil, 5-15 mil, 5-20 mil, 5-25 mil,5-30 mil, 5-40 mil, 5-50 mil, 5-60 mil, 5-70 mil, 5-75 mil, 5-80 mil,5-90 mil, 5-100 mil, 10-15 mil, 10-20 mil, 10-25 mil, 10-30 mil, 10-40mil, 10-50 mil, 10-60 mil, 10-70 mil, 10-75 mil, 10-80 mil, 10-90 mil,10-100 mil, 15-20 mil, 15-25 mil, 15-30 mil, 15-40 mil, 15-50 mil, 15-60mil, 15-70 mil, 15-75 mil, 15-80 mil, 15-90 mil, 15-100 mil, 20-25 mil,20-30 mil, 20-40 mil, 20-50 mil, 20-60 mil, 20-70 mil, 20-75 mil, 20-80mil, 20-90 mil, 20-100 mil, 25-30 mil, 25-40 mil, 25-50 mil, 25-60 mil,25-70 mil, 25-75 mil, 25-80 mil, 25-90 mil, 25-100 mil, 30-40 mil, 30-50mil, 30-60 mil, 30-70 mil, 30-75 mil, 30-80 mil, 30-90 mil, 30-100 mil,40-50 mil, 40-60 mil, 40-70 mil, 40-75 mil, 40-80 mil, 40-90 mil, 40-100mil, 50-60 mil, 50-70 mil, 50-75 mil, 50-80 mil, 50-90 mil, 50-100 mil,50-70 mil, 50-75 mil, 50-80 mil, 50-90 mil, 50-100 mil, 60-70 mil, 60-75mil, 60-80 mil, 60-90 mil, 60-100 mil, 70-75 mil, 70-80 mil, 70-90 mil,70-100 mil, 75-80 mil, 75-90 mil, 75-100 mil, 80-90 mil, 80-100 mil, or90-100 mil.

The first layer is a protective outer layer which serves at least toprotect the patch. In some embodiments, the first layer overlays oroverhangs at least one edge of at least one of the second layer, thirdlayer, or the adhesive/drug layer. In embodiments, the first layer iscomprised of a woven or non-woven fabric, a woven or non-woven polymerfabric, a polymer film, which may be elastic, an occlusive polymer film,a polymer laminate and a polymer/metal laminate. A woven fabric isgenerally produced from warp and weft polymeric or natural fibers.Exemplary woven or non-woven fabrics are polyester fabrics. Oneexemplary woven fabric is a bi-elastic polyester fabric such as the KOB053 available from Karl Otto GmbH & Co. In some embodiments, the polymerfilm is an elastic polymer film.

In some embodiments, the first layer is comprised of one or morestretchable polymers. In some embodiments, the first layer is comprisedof one or more polymers having a low shear strength or resistance. Theshear strength may be measured by any methods as known in the art. Someexemplary methods of testing or measuring shear strength include thepunch technique or test and the losipescu test as known to those skilledin the art. In some embodiments, the shear strength may be measuredusing a viscometer.

In some embodiments, the shear strength is expressed in terms of apercentage of the tensile strength of the polymer(s). In somenon-limiting embodiments, one or more of the polymers of the secondlayer have a shear strength that is or is less than about 1-25% of itstensile strength. In some embodiments, one or more of the polymers has ashear strength that is or is less than about 1-20%, 1-15%, 1-10%, 1-5%,5-25%, 5-20%, 5-15%, 5-10%, 10-25%, 10-20%, 10-15%, 15-25%, 15-20%, or20-25% of the tensile strength for the polymer. In some specific, butnot limiting embodiments, one or more of the polymers has a shearstrength that is or is less than about 1%, 5%, 10%, 15%, 20%, 25%, 30%,or 40% of the tensile strength for the polymer. In some embodiments, theshear strength is about or less than about 0.1-15 MPa. In someembodiments, the shear strength is about or less than about 0.1-10 MPa,0.1-9 MPa, 0.1-8 MPa, 0.1-7 MPa, 0.1-6 MPa, 0.1-5 MPa, 0.1-4 MPa, 0.1-3MPa, 0.1-2 MPa, 0.1-1 MPa, 0.1-0.5 MPa, 0.5-15 MPa, 0.5-10 MPa, 0.5-9MPa, 0.5-8 MPa, 0.5-7 MPa, 0.5-6 MPa, 0.5-5 MPa, 0.5-4 MPa, 0.5-3 MPa,0.5-2 MPa, 0.5-1 MPa, 1-15 MPa, 1-10 MPa, 1-9 MPa, 1-8 MPa, 1-7 MPa, 1-6MPa, 1-5 MPa, 1-4 MPa, 1-3 MPa, 1-2 MPa, 2-15 MPa, 2-10 MPa, 2-9 MPa,2-8 MPa, 2-7 MPa, 2-6 MPa, 2-5 MPa, 2-4 MPa, 2-3 MPa, 3-15 MPa, 3-10MPa, 3-9 MPa, 3-8 MPa, 3-7 MPa, 3-6 MPa, 3-5 MPa, 3-4 MPa, 4-15 MPa,4-10 MPa, 4-9 MPa, 4-8 MPa, 4-7 MPa, 4-6 MPa, 4-5 MPa, 5-15 MPa, 5-10MPa, 5-9 MPa, 5-8 MPa, 5-7 MPa, 5-6 MPa, 6-15 MPa, 6-10 MPa, 6-9 MPa,6-8 MPa, 6-7 MPa, 7-15 MPa, 7-10 MPa, 7-9 MPa, 7-8 MPa, 8-15 MPa, 8-10MPa, 8-9 MPa, 9-15 MPa, 9-10 MPa, or 10-15 MPa.

Suitable polymers are known in the art and include elastomers,polyesters, polyethylenes, polypropylenes, polyurethanes, polyetheramides and copolymers thereof. In some embodiments, the polymer ispolyethylene vinyl acetate, polyvinylchloride or copolymers thereof. Insome embodiments, the first layer is comprised of one or more ofpolyethylene terephthalate, polyvinyl acetate, polyvinylidene chloride,polyvinylchloride, and polyethylene vinyl acetate or copolymers thereof.Polymer/metal laminates are known in the art and include aluminumlaminates and tin laminates, among others. In some embodiments, thefirst layer is comprised of a laminate. In one non-limiting embodiment,the first layer is comprised of a polyethylene and polyester laminatesuch as the laminate sold under the name Scotchpak™ #9723. In someembodiments, the first layer is formed of a polyurethane film, athermoplastic polyester elastomer such as a Hytrel® film available fromDuPont®, or a polyethylene vinyl acetate film. In some embodiments, atleast the first layer of the backing layer is occlusive.

In some embodiments, the first layer is a stretchable, elastic and/orflexible layer comprised of one or more polymers having a stretchabilityand/or elasticity of at least about 5% in at least one direction. Inthis embodiment, the first layer, along with the second or middle layerabsorbs the stress of the movement of the adhesive drug layer or deviceagainst the skin or other administration site. In some embodiments, thefirst layer is comprised of one or more stretchable polymers having astretchability and/or elasticity of at least about 5% or at least about10% in at least one direction. The stretchability may be ascertained byany suitable means as known in the art. In some embodiments, thestretchability is determined at room temperature or at approximately20-25° C. In embodiments, the first layer is comprised of one or morestretchable polymers having a stretchability and/or elasticity of atleast about 5-50%. In some embodiments, the first layer is comprised ofone or more stretchable polymers having a stretchability and/orelasticity of at least about 5-40%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%,10-50%, 10-40%, 10-30%, 10-25%, 10-20%, 10-15%, 15-50%, 15-40%, 15-30%,15-25%, 15-20%, 20-50%, 20-40%, 20-30%, 20-25%, 25-50%, 25-40%, 25-30%,30-50%, 30-40%, or 40-50%. In specific, but not limiting embodiments,the first layer is comprised of one or more stretchable polymers havinga stretchability and/or elasticity of at least about 5%, 10%, 15%, 20%,25%, 30%, 40%, or 50%. In some embodiments, the first layer isstretchable, but not elastic. In other embodiments, the first layer isrelatively stiff.

In embodiments, the first layer has a thickness of about 0.2-50 mil. Innon-limiting embodiments, the first layer has a thickness of betweenabout 0.2-0.5 mil, 0.2-1 mil, 0.2-1.5 mil, 0.2-2 mil, 0.2-5 mil, 0.2-10mil, 0.2-15 mil, 0.2-20 mil, 0.2-25 mil, 0.2-30 mil, 0.2-35 mil, 0.2-40mil, 0.2-45 mil, 0.5-0.75 mil, 0.5-1 mil, 0.5-1.5 mil, 0.5-2 mil,0.5-2.5 mil, 0.5-3 mil, 0.5-4 mil, 0.5-5 mil, 0.5-6 mil, 0.5-7 mil,0.5-8 mil, 0.5-9 mil, 0.5-10 mil, 0.5-15 mil, 0.5-20 mil, 0.5-25 mil,0.5-30 mil, 0.5-35 mil, 0.5-40 mil, 0.5-45 mil, 0.5-50 mil, 0.75-1 mil,0.75-1.5 mil, 0.75-2 mil, 0.75-2.5 mil, 0.75-3 mil, 0.75-4 mil, 0.75-5mil, 0.75-6 mil, 0.75-7 mil, 0.75-8 mil, 0.75-9 mil, 0.75-10 mil,0.75-15 mil, 0.75-20 mil, 0.75-25 mil, 0.75-30 mil, 0.75-35 mil, 0.75-40mil, 0.75-45 mil, 0.75-50 mil, 1-1.5 mil, 1-2 mil, 1-2.5 mil, 1-3 mil,1-4 mil, 1-5 mil, 1-6 mil, 1-7 mil, 1-8 mil, 1-9 mil, 1-10 mil, 1-15mil, 1-20 mil, 1-25 mil, 1-30 mil, 1-35 mil, 1-40 mil, 1-45 mil, 1-50mil, 1.5-2 mil, 1.5-2.5 mil, 1.5-3 mil, 1.5-4 mil, 1.5-5 mil, 1.5-6 mil,1.5-7 mil, 1.5-8 mil, 1.5-9 mil, 1.5-10 mil, 1.5-15 mil, 1.5-20 mil,1.5-25 mil, 1.5-30 mil, 1.5-35 mil, 1.5-40 mil, 1.5-45 mil, 1.5-50 mil,2-2.5 mil, 2-3 mil, 2-4 mil, 2-5 mil, 2-6 mil, 2-7 mil, 2-8 mil, 2-9mil, 2-10 mil, 2-15 mil, 2-20 mil, 2-25 mil, 2-30 mil, 2-35 mil, 2-40mil, 2-45 mil, 2-50 mil, 2.5-3 mil, 2.5-4 mil, 2.5-5 mil, 2.5-6 mil,2.5-7 mil, 2.5-8 mil, 2.5-9 mil, 2.5-10 mil, 2.5-15 mil, 2.5-20 mil,2.5-25 mil, 2.5-30 mil, 2.5-35 mil, 2.5-40 mil, 2.5-45 mil, 2.5-50 mil,3-4 mil, 3-5 mil, 3-6 mil, 3-7 mil, 3-8 mil, 3-9 mil, 3-10 mil, 3-15mil, 3-20 mil, 3- 25 mil, 3-30 mil, 3-35 mil, 3-40 mil, 3-45 mil, 3-50mil, 4-5 mil, 4-6 mil, 4-7 mil, 4-8 mil, 4-9 mil, 4-10 mil, 4-15 mil,4-20 mil, 4-25 mil, 4-30 mil, 4-35 mil, 4-40 mil, 4-45 mil, 4-50 mil,5-6 mil, 5-7 mil, 5-8 mil, 5-9 mil, 5-10 mil, 5-15 mil, 5-20 mil, 5-25mil, 5-30 mil, 5-35 mil, 5-40 mil, 5-45 mil, 5-50 mil, 6-7 mil, 6-8 mil,6-9 mil, 6-10 mil, 6-15 mil, 6-20 mil, 6-25 mil, 6-30 mil, 6-35 mil,6-40 mil, 6-45 mil, 6-50 mil, 7-8 mil, 7-9 mil, 7-10 mil, 7-15 mil, 7-20mil, 7-25 mil, 7-30 mil, 7-35 mil, 7-40 mil, 7-45 mil, 7-50 mil, 8-9mil, 8-10 mil, 8-15 mil, 8-20 mil, 1-25 mil, 8-30 mil, 8-35 mil, 8-40mil, 8-45 mil, 8-50 mil, 9-10 mil, 9-15 mil, 9-20 mil, 10-15 mil, 10-20mil, 10-25 mil, 10-30 mil, 10-35 mil, 10-40 mil, 10-45 mil, 10-50 mil,20-25 mil, 20-30 mil, 20-35 mil, 20-40 mil, 20-45 mil, 20-50 mil, 25-30mil, 25-35 mil, 25-40 mil, 25-45 mil, 25-50 mil, 30-35 mil, 30-40 mil,30-45 mil, 30-50 mil, 35-40 mil, 35-45 mil, 35-50 mil, 40-45 mil, 40-50mil, or 45-50 mil. In specific non-limiting embodiments, the first layerhas a thickness of about 0.5 mil, 0.75 mil, 1 mil, 1.5 mil, 2 mil, 3mil, 4 mil, 5 mil, 6 mil, 7 mil, 8 mil, 9 mil, 10 mil, 15 mil, or 20mil.

The composite backing layer further comprises a second or middle layer20 adjacent the first or top layer. The second layer is preferably anadhesive, tie or binding layer positioned between the first and thirdlayers. The second layer serves to adhere, attach or bind the first andthird layers. In some embodiments, one of the first or third layers maybe relatively stiff and/or stationary and the other of the first andthird layer may be flexible and/or elastic. The second layer, along withthe flexible or relatively flexible layer absorbs the stress of theadhesive drug layer against the skin or other administration site. Inembodiments, the second layer is comprised of polymers having a tensileor yield strength of less than about 5 MPa or about 10 MPa. The tensilestrength is a measurement of the force required per unit area (MPa) atthe break point of the polymer. In some embodiments, the second layer iscomprised of one or more polymers having a tensile strength of less thanabout 5-10 MPa. In some embodiments, the second layer is comprised ofone or more polymers having a tensile strength of less than about 6-10MPa, 7-10 MPa, 8-10 MPa, or 9-10 MPa. In some embodiments, the secondlayer is comprised of polymers such that the second layer as a whole hasa tensile strength of less than about 10 MPa. The tensile or yieldstrength may be ascertained by any suitable means as known in the art.In one embodiment, the tensile or yield strength is determined by theASTM D882 test which comprising pulling a polymer sample from both endsto determine the force required at the yield or break point. In someembodiments, the tensile strength is the tensile strength at roomtemperature or at approximately 20-25° C. In embodiments, the secondlayer is comprised of polymers having an elongation of not less than orat least about 10%. In some embodiments, the second layer is comprisedof polymers having an elongation of not less than or at least about 50%.The elongation refers to the percentage of elongation before the polymerbreaks under an applied strain. In embodiments, the % elongation is thefinal length (L) of the polymer or polymer material after stretching,minus the initial length (L_(i)) divided by the initial length. The %elongation may be ascertained by any suitable means as known in the art.In some embodiments, the % elongation is determined at room temperatureor at approximately 20-25° C. In some embodiments, the second layer iscomprised of polymers such that the second layer as a whole has a %elongation of at least about or not less than about 10% or about 50%. Insome embodiments, the second layer is comprised of one or more polymershaving a % elongation of at least about 10-500%. In some embodiments,the second layer is comprised of one or more polymers having a %elongation of at least about 10-75%, 10-100%, 10-150%, 10-200%, 10-250%,10-300%, 10-400%, 50-75%, 50-100%, 50-150%, 50-200%, 50-250%, 50-300%,50-400%, 50-500%, 75-100%, 75-150%, 75-200%, 75-250%, 75-300%, 75-400%,75-500%, 100-150%, 100-200%, 100-250%, 100-300%, 100-400%, 100-500%,150-200%, 150-250%, 150-300%, 150-400%, 150-500%, 200-250%, 200-300%,200-400%, 200-500%, 250-300%, 250-400%, 250-500%, 300-400%, 300-500%,400-500% or more.

In some embodiments, the second layer is comprised of one or morepolymers having a low shear strength. Shear strength refers to thepolymer's ability to resist forces that cause the internal structure toslide against itself. In some embodiments, the shear strength isexpressed in terms of a percentage of the tensile strength of thepolymer(s). In some non-limiting embodiments, one or more of thepolymers of the second layer have a shear strength that is or is lessthan about 1-25% of its tensile strength. In some embodiments, one ormore of the polymers has a shear strength that is or is less than about1-20%, 1-15%, 1-10%, 1-5%, 5-25%, 5-20%, 5-15%, 5-10%, 10-25%, 10-20%,10-15%, 15-25%, 15-20%, or 20-25% of the tensile strength for thepolymer. In some specific, but not limiting embodiments, one or more ofthe polymers has a shear strength that is or is less than about 1%, 5%,10%, 15%, 20%, 25%, 30%, or 40% of the tensile strength for the polymer.In some embodiments, the shear strength is about or less than about0.1-15 MPa. In some embodiments, the shear strength is about or lessthan about 0.1-10 MPa, 0.1-9 MPa, 0.1-8 MPa, 0.1-7 MPa, 0.1-6 MPa, 0.1-5MPa, 0.1-4 MPa, 0.1-3 MPa, 0.1-2 MPa, 0.1-1 MPa, 0.1-0.5 MPa, 0.5-15MPa, 0.5-10 MPa, 0.5-9 MPa, 0.5-8 MPa, 0.5-7 MPa, 0.5-6 MPa, 0.5-5 MPa,0.5-4 MPa, 0.5-3 MPa, 0.5-2 MPa, 0.5-1 MPa, 1-15 MPa, 1-10 MPa, 1-9 MPa,1-8 MPa, 1-7 MPa, 1-6 MPa, 1-5 MPa, 1-4 MPa, 1-3 MPa, 1-2 MPa, 2-15 MPa,2-10 MPa, 2-9 MPa, 2-8 MPa, 2-7 MPa, 2-6 MPa, 2-5 MPa, 2-4 MPa, 2-3 MPa,3-15 MPa, 3-10 MPa, 3-9 MPa, 3-8 MPa, 3-7 MPa, 3-6 MPa, 3-5 MPa, 3-4MPa, 4-15 MPa, 4-10 MPa, 4-9 MPa, 4-8 MPa, 4-7 MPa, 4-6 MPa, 4-5 MPa,5-15 MPa, 5-10 MPa, 5-9 MPa, 5-8 MPa, 5-7 MPa, 5-6 MPa, 6-15 MPa, 6-10MPa, 6-9 MPa, 6-8 MPa, 6-7 MPa, 7-15 MPa, 7-10 MPa, 7-9 MPa, 7-8 MPa,8-15 MPa, 8-10 MPa, 8-9 MPa, 9-15 MPa, 9-10 MPa, or 10-15 MPa.

In embodiments, the one or more polymers are selected from acrylates andacrylate copolymers, polyisobutylenes, silicone, polystyrene butylrubber, polyethylene vinyl acetate and copolymers thereof. In someembodiments, the second layer is comprised of an adhesive selected fromacrylic adhesives, polyisobutylene adhesives, or silicone adhesives. Insome embodiments, the adhesive is a pressure sensitive adhesive. In someembodiments, the second layer is comprised of plasticized polymers.

In embodiments, the second layer has a thickness of about 0.5-30 mil. Innon-limiting embodiments, the second layer has a thickness of betweenabout 0.5-0.75 mil, 0.5-1 mil, 0.5-1.5 mil, 0.5-2 mil, 0.5-2.5 mil,0.5-3 mil, 0.5-4 mil, 0.5-5 mil, 0.5-6 mil, 0.5-7 mil, 0.5-8 mil, 0.5-9mil, 0.5-10 mil, 0.5-15 mil, 0.5-20 mil, 0.5-25 mil, 0.75-1 mil,0.75-1.5 mil, 0.75-2 mil, 0.75-2.5 mil, 0.75-3 mil, 0.75-4 mil, 0.75-5mil, 0.75-6 mil, 0.75-7 mil, 0.75-8 mil, 0.75-9 mil, 0.75-10 mil,0.75-15 mil, 0.75-20 mil, 0.75-25 mil, 0.75-30 mil, 1-1.5 mil, 1-2 mil,1-2.5 mil, 1-3 mil, 1-4 mil, 1-5 mil, 1-6 mil, 1-7 mil, 1-8 mil, 1-9mil, 1-10 mil, 1-15 mil, 1-20 mil, 1-25 mil, 1-30 mil, 1.5-2 mil,1.5-2.5 mil, 1.5-3 mil, 1.5-4 mil, 1.5-5 mil, 1.5-6 mil, 1.5-7 mil,1.5-8 mil, 1.5-9 mil, 1.5-10 mil, 1.5-15 mil, 1.5-20 mil, 1.5-25 mil,1.5-30 mil, 2-2.5 mil, 2-3 mil, 2-4 mil, 2-5 mil, 2-6 mil, 2-7 mil, 2-8mil, 2-9 mil, 2-10 mil, 2-15 mil, 2-20 mil, 2-25 mil, 2-30 mil, 2.5-3mil, 2.5-4 mil, 2.5-5 mil, 2.5-6 mil, 2.5-7 mil, 2.5-8 mil, 2.5-9 mil,2.5-10 mil, 2.5-15 mil, 2.5-20 mil, 2.5-25 mil, 2.5-30 mil, 3-4 mil, 3-5mil, 3-6 mil, 3-7 mil, 3-8 mil, 3-9 mil, 3-10 mil, 3-15 mil, 3-20 mil,3-25 mil, 3-30 mil, 4- 5 mil, 4-6 mil, 4-7 mil, 4-8 mil, 4-9 mil, 4-10mil, 4-15 mil, 4-20 mil, 4-25 mil, 4-30 mil, 5-4 mil, 5- 5 mil, 5-6 mil,5-7 mil, 5-8 mil, 5-9 mil, 5-10 mil, 5-15 mil, 5-20 mil, 5-25 mil, 5-30mil, 6-7 mil, 6- 8 mil, 6-9 mil, 6-10 mil, 6-15 mil, 6-20 mil, 6-25 mil,6-30 mil, 7-8 mil, 7-9 mil, 7-10 mil, 7-15 mil, 7-20 mil, 7-25 mil, 7-30mil, 8-9 mil, 8-10 mil, 8-15 mil, 8-20 mil, 8-25 mil, 8-30 mil, 9-10mil, 9-15 mil, 9-20 mil, 9-25 mil, 9-30 mil, 10-15 mil, 10-20 mil, 10-25mil, 10-30 mil, 15-20 mil, 15-25 mil, 15-30 mil, 20-25 mil, 20-30 mil,or 25-30 mil. In specific non-limiting embodiments, the second layer hasa thickness of about 0.5 mil, 0.75 mil, 1 mil, 1.5 mil, 2 mil, 3 mil, 4mil, 5 mil, 6 mil, 7 mil, 8 mil, 9 mil, 10 mil, 15 mil, 20 mil, 25 mil,or 30 mil.

The composite backing layer further comprises a third or bottom layeradjacent the second or middle layer. In some embodiments, the thirdlayer is a stretchable and/or flexible layer. In embodiments, the thirdlayer, along with the second or middle layer absorbs the stress of themovement of the adhesive drug layer against the skin or otheradministration site. In some embodiments, the third layer is comprisedof one or more stretchable polymers having a stretchability and/orelasticity of at least about 5% or at least about 10% in at least onedirection. The stretchability may be ascertained by any suitable meansas known in the art. In some embodiments, the stretchability isdetermined at room temperature or at approximately 20-25° C. Inembodiments, the third layer is comprised of one or more stretchablepolymers having a stretchability or elasticity of at least about 5-50%.In some embodiments, the third layer is comprised of one or morestretchable polymers having a stretchability or elasticity of at leastabout 5-40%, 5-30%, 5-25%, 5-20%, 5-15%, 5-10%, 10-50%, 10-40%, 10-30%,10-25%, 10-20%, 10-15%, 15-50%, 15-40%, 15-30%, 15-25%, 15-20%, 20-50%,20-40%, 20-30%, 20-25%, 25-50%, 25-40%, 25-30%, 30-50%, 30-40%, or40-50%. In specific, but not limiting embodiments, the third layer iscomprised of one or more stretchable polymers having a stretchability orelasticity of at least about 5%, 10%, 15%, 20%, 25%, 30%, 40%, or 50%.

In other embodiments, the third layer is relatively stiff as compared toat least one of the first or second layers.

In some embodiments, the third layer is occlusive or substantiallyocclusive. In other embodiments, the third layer is breathable.

In embodiments, the third layer has a thickness of about 0.5-40 mil. Innon-limiting embodiments, the third layer has a thickness of betweenabout 0.5-1 mil, 0.5-1.5 mil, 0.5-2 mil, 0.5-3 mil, 0.5-4 mil, 0.5-5mil, 0.5-10 mil, 0.5-15 mil, 0.5-20 mil, 0.5-25 mil, 0.5-30 mil, 0.5-35mil, 1-1.5 mil, 1-2 mil, 1-3 mil, 1-4 mil, 1-5 mil, 1-10 mil, 1-15 mil,1-20 mil, 1-25 mil, 1-30 mil, 1-35 mil, 1-40 mil. 1.5-2 mil, 1.5-3 mil,1.5-4 mil, 1.5-5 mil, 1.5-10 mil, 1.5-15 mil, 1.5-20 mil, 1.5-25 mil,1.5-30 mil, 1.5-35 mil, 1.5-40 mil, 2-3 mil, 2-4 mil, 2-5 mil, 2-10 mil,2-15 mil, 2-20 mil, 2-25 mil, 2-30 mil, 2-35 mil, 2-40 mil, 3-4 mil, 3-5mil, 3-10 mil, 3-15 mil, 3-20 mil, 3-25 mil, 3-30 mil, 3-35 mil, 3-40mil, 4-5 mil, 4-10 mil, 4-15 mil, 4-20 mil, 4-25 mil, 4-30 mil, 4-35mil, 4-40 mil, 5-10 mil, 5-15 mil, 5-20 mil, 5-25 mil, 5-30 mil, 5-35mil, 5-40 mil, 10-15 mil, 10-20 mil, 10-25 mil, 10-30 mil, 10-35 mil,10-40 mil, 15-20 mil, 15-25 mil, 15-30 mil, 15-35 mil, 15-40 mil, 20-25mil, 20-30 mil, 20-35 mil, 20-40 mil, 25-30 mil, 25-35 mil, 25-40 mil,30-35 mil, 30-40 mil, or 35-40 mil. In specific, but not limitingembodiments, the third layer has a thickness of about 0.5 mil, 1 mil,1.5 mil, 2 mil, 3 mil, 4 mil, 5 mil, 10 mil, 15 mil, 20 mil, 25 mil, 30mil, 35 mil, or 40 mil.

In embodiments, the third layer is a non-woven or woven fabric formed ofsynthetic or natural fibers. In embodiments, the synthetic fibers arecomprised of one or more polymer fibers. In embodiments, the third layeris a polymer film, polymer laminate, or polymer matrix. In embodiments,the polymer is selected from one or more of polyesters such aspolyethylene terephthalate (PET), polyethylenes, vinyl acetates orcopolymers thereof, polypropylenes, nylon, polystyrenes,polyvinylchloride, or polyurethanes, ethylene vinyl acetate (EVA)copolymers thereof, or mixtures/blends thereof. In embodiments, thethird layer is a polymer film comprised of a polyethyleneterephthalate/ethylene vinyl acetate laminate. In other embodiments, thethird layer is comprised of polyethylene terephthalate. In embodiments,the natural fibers are comprised of at least one of cotton or silk. Thethird layer is attached or affixed to an adhesive/drug layer using anysuitable means. In some embodiments, the third layer is affixed orattached to the adhesive/drug layer using a suitable adhesive.

Example 1 describes preparation of an exemplary transdermal deliverysystem comprising a composite backing layer. A stretchable or flexiblepolymer layer is laminated onto an occlusive backing using an adhesive.An adhesive formulation is prepared, coated onto a release liner and theformulation is laminated onto the polymer side of the composite backinglaminate. Example 7 describes preparation of a further exemplarytransdermal delivery system comprising a composite backing layer. Astretchable, woven fabric is laminated onto a polymer film using anadhesive. An adhesive drug formulation is prepared, coated onto arelease liner and the formulation is laminated onto the polymer filmside of the composite backing laminate.

In a second aspect, one or more layers of the composite backing is atleast partially cut, incised or divided. In some embodiments, at leastone layer comprises multiple cuts, incisions, or divisions through thelayer such that at least one layer of the composite comprises several,separate pieces. FIG. 5 is a side view illustrating an exemplarycomposite backing comprising separate pieces for a first or top layer.In this aspect, the composite backing 26 comprises a first layer 28, asecond adhesive layer 30, and a third layer 32 that may be occlusive orbreathable. Any combination or all of the layers of the compositebacking may be at least partially cut, incised or divided. Inembodiments, at least one of the first layer or the third layer is atleast partially cut, incised or divided. In embodiments, at least thethird occlusive or breathable layer comprises separate pieces as shownin FIG. 5 .

As seen FIG. 4A, one or more layers of the composite backing is at leastpartially cut, incised or divided. In some embodiments, at least thethird layer 32 of the composite backing is at least partially cut,incised or divided. In the embodiment as shown in FIGS. 4A-4B, the thirdlayer is at least partially cut, incised or divided such that the thirdlayer is comprised of a plurality of portions or pieces. These cuts maybe formed partially or completely through the layer. In an embodiment,the layer is kiss cut such that at least one layer is cut while at leastone of the layers (e.g. an elastic, flexible or stretchable layer)remains at least partially intact. In embodiments, the elastic orflexible polymer layer holds the layer comprising the cuts or incisions.In some embodiments, both the elastic, flexible or stretchable layer andthe adhesive layers are at least partially intact. FIG. 4A shows anexemplary grid pattern for the cuts or incisions 36. In someembodiments, the cut layer is comprised of individually separated piecesof material 34 formed by the cuts in the layer material. The separatepieces may be any appropriate shape or form. In embodiments, theseparated pieces are rectangular or square. It will be appreciated thatthe cuts may be regular or irregular in shape. It will further beappreciated that the resulting pieces may be the same or differentshapes. In some embodiments, one or more of the pieces are connected atone or more connection regions. FIG. 4B shows a layer formed ofindividual rectangular pieces of material. In some embodiments, the cutlayer is formed of multiple pieces of a relatively stiff material asdescribed above. Motion of the relatively stiff layer within thecomposite and/or against the skin will be dissipated at the cuts. Thelayer comprising the cuts/pieces will behave like multiple patches ofsmaller area applied. Where the cut layer is formed of separate pieces,the layer is conformable and/or stretchable along with the movement ofskin. Further, the adhesion of each piece helps an adjacent piecebecause they are held or adhered together similar to a continuous layer.

In some embodiments, each piece of the cut layer has a surface area ofbetween about 5-50 cm². In some embodiments, each piece of the cut layerhas a surface area of between about 10-30 cm². In some embodiments, eachpiece has a surface area of about 10 cm², 15 cm², 20 cm², 25 cm², 30cm², 35 cm², 40 cm², 45 cm², or 50 cm². In some embodiments, the piecesof the layer may comprise a similar size. In other embodiments, thepieces of the layer comprise different sizes.

In some embodiments, the cuts, incisions or divisions extend at leastpartially along a planar surface of at least one layer of the compositebacking. FIG. 9 is a top down view of a device as described herein insome embodiments. As seen in this embodiment, the cuts, incisions ordivisions 70 extend along a portion of one or more layers 68 of thedevice, but do not extend across or along the entirety of the layer. Inthis embodiment, the cuts, incisions or divisions do not intersect.Instead, the layer(s) are intact at one or more of the edges and/or theareas where cross-wise cuts, incisions or divisions would intersect 72.Rather than being separate pieces, the partially cut portions of thelayer 76 are at least partially connected. This embodiment further showsthe overhang of the first layer 66.

Example 2 describes preparation of an exemplary layer comprising adiscretely cut layer. A flexible polymer material is applied to acarrier formed of paper or other inert material. The carrier serves as asubstrate to form the discretely cut layer. In embodiments, the flexiblepolymer is as described above including, but not limited to, a thin(0.5-1.0 mil) polyurethane film. An occlusive material is applied to theflexible polymer material using a suitable adhesive as known in the art.In some embodiments, the adhesive is selected from a polyisobutylene(PIB), an acrylate or acrylate co-polymer, or a silicone adhesive orbinding agent. The resulting laminate comprises the carrier, flexiblepolymer, adhesive, and occlusive material. The laminate is at leastpartially cut such that the occlusive layer is separated into separatedpieces. At least a portion of the flexible polymer layer remains intact.

Example 3 describes preparation of a transdermal delivery system using acomposite backing layer comprising an occlusive layer kiss-cut intorectangular pieces.

The device includes at least one adhesive/drug layer 14 adjacent thecomposite backing layer 12. In embodiments, the adhesive layer is anadhesive matrix comprising the active agent as described above. Theadhesive layer adheres to the backing layer and/or skin at theadministration site. Preferably, the adhesive layer 14 is positionedadjacent the third or bottom layer 22 of the composite backing 12. Theadhesive layer matrix serves to release the active agent to the skin aswell as secure the patch to the skin.

In an embodiment, the adhesive/drug layer is an adhesivehydrogel-containing composition as described in U.S. Pat. No. 8,728,445,which is incorporated herein by reference. One suitablehydrogel-containing composition is comprised of a single, continuoushydrophilic phase. Another suitable composition comprises adiscontinuous hydrophobic phase and a hydrophilic phase that is eithercontinuous or discontinuous. In an embodiment, the hydrogel compositioncomprises a discontinuous hydrophobic phase comprising at least onehydrophobic polymer, a plasticizer such as an elastomer, a tackifyingresin and/or other excipients; and a hydrophilic phase comprised of atleast one crosslinked hydrophilic polymer.

The hydrophobic polymer may be a hydrophobic pressure-sensitive adhesive(PSA) polymer. In some embodiments, the hydrophobic polymer is athermosetting polymer. In embodiments, the hydrophobic PSA polymers arecrosslinked butyl rubbers, wherein a “butyl rubber,” as well known inthe art, is an isoprene-isobutylene copolymer typically having anisoprene content in the range of about 0.5 to 3 wt %, or a vulcanized ormodified version thereof, e.g., a halogenated (brominated orchlorinated) butyl rubber. In some embodiments, the hydrophobic PSApolymer is butyl rubber crosslinked with polyisobutylene. Other suitablehydrophobic polymers include, for example, natural rubber adhesives,vinyl ether polymers, polysiloxanes, polyisoprene, butadieneacrylonitrile rubber, polychloroprene, atactic polypropylene, andethylene-propylene-diene terpolymers (also known as “EPDM” or “EPDMrubber”) (available as Trilene® 65 and Trilene® 67 from UniroyalChemical Co., Middlebury, Conn.). Still other suitable hydrophobic PSAswill be known to those of ordinary skill in the art and/or are describedin the pertinent texts and literature. See, for example, the Handbook ofPressure-Sensitive Adhesive Technology, 2nd Ed., Satas, Ed. (New York:Von Nostrand Reinhold, 1989). In some particular embodiments, thehydrophobic polymers are the crosslinked butyl rubbers available in theKalar® series from Elementis Specialties, Inc. (Hightstown, N.J.),including Kalar® 5200, Kalar® 5215, Kalar® 5246, and Kalar® 5275.

In some embodiments, the hydrophobic phase comprises a plasticizer. By“plasticizer” is meant that the component tends to decrease the glasstransition temperature of the hydrophobic polymer and/or reduce its meltviscosity. Suitable plasticizing elastomers are natural and syntheticelastomeric polymers, including, for example, AB, ABA, and “multiarmed”(AB)x block copolymers, where for example, A is a polymerized segment or“block” comprising aryl-substituted vinyl monomers, preferably styrene,α-methyl styrene, vinyl toluene, and the like, B is an elastomeric,conjugated polybutadiene or polyisoprene block, and x has a value of 3or more. In some embodiments, the plasticizer is an elastomer includingbutadiene-based and isoprene-based polymers, particularlystyrene-butadiene-styrene (SBS), styrene-butadiene (SB),styrene-isoprene-styrene (SIS), and styrene-isoprene (SI) blockcopolymers, where “S” denotes a polymerized segment or “block” ofstyrene monomers, “B” denotes a polymerized segment or block ofbutadiene monomers, and “I” denotes a polymerized segment or block ofisoprene monomers. Other suitable elastomers include radial blockcopolymers having a SEBS backbone (where “E” and “B” are, respectively,polymerized blocks of ethylene and butylene) and I and/or SI arms.Natural rubber (polyisoprene) and synthetic polyisoprene can also beused.

In some embodiments, the hydrophobic phase comprises a tackifying resin.The tackifying resin may be a relatively low molecular weight resin(weight average molecular weight generally less than about 50,000)having a fairly high glass transition temperature. Tackifying resinsinclude, for example, rosin derivatives, terpene resins, and syntheticor naturally derived petroleum resins. In some embodiments, thetackifying resin is selected from the group of non-polar tackifyingresins, such as Regalrez® 1085 (a hydrogenated hydrocarbon resin) andRegalite® Resins such as Regalite® 1900, available from Hercules,Escorez® 1304 (also a hydrocarbon resins) and Escorez® 1102 availablefrom Exxon Chemical Company, Wingtack® 95 (a synthetic polyterpeneresin), or Wingtack® 85, available from Goodyear Tire and Rubber.

In some embodiments, the hydrophobic phase comprises an optionalantioxidant which serves to enhance the oxidative stability of thehydrogel composition. Other suitable plasticizers, tackifiers, andantioxidants are known in the art such as those described in U.S. Pat.No. 8,728,445, which is incorporated herein by reference.

In some embodiments, the composition comprises a discontinuoushydrophilic phase comprised of at least one crosslinked hydrophilicpolymer that is insoluble in water under standard conditions of storageand use, but is water-swellable. In embodiments, the degree ofcrosslinking is selected so that the polymer will not melt duringmanufacture of the composition. Suitable hydrophilic polymers include,but are not limited to: crosslinked cellulosic polymers (such ascrosslinked sodium carboxymethylcellulose); crosslinked acrylatepolymers and copolymers; carbomers, i.e., hydroxylated vinylic polymersalso referred to as “interpolymers,” which are prepared by crosslinkinga monoolefinic acrylic acid monomer with a polyalkyl ether of sucrose(commercially available under the trademark Carbopol® from the B. F.Goodrich Chemical Company); crosslinked acrylamide-sodium acrylatecopolymers; gelatin; vegetable polysaccharides, such as alginates,pectins, carrageenans, or xanthan; starch and starch derivatives; andgalactomannan and galactomannan derivatives. One particular crosslinkedhydrophilic polymer is crosslinked sodium CMC, available as Aquasorb®A500 from Aqualon, a division of Hercules, Inc.

In some embodiments, the composition comprises a continuous hydrophilicphase. The continuous hydrophilic phase comprises a water-swellable,water-insoluble polymer, a blend of a hydro hydrophilic polymer and acomplementary oligomer capable of hydrogen bonding thereto, and anoptional low molecular weight plasticizer.

The water-swellable, water-insoluble polymer is generally capable of atleast some degree of swelling when immersed in an aqueous liquid but isinsoluble in water within a selected pH range, generally up to a pH ofat least about 7.5 to 8.5. The polymer may be comprised of a celluloseester, for example, cellulose acetate, cellulose acetate propionate(CAP), cellulose acetate butyrate (CAB), cellulose propionate (CP),cellulose butyrate (CB), cellulose propionate butyrate (CPB), cellulosediacetate (CDA), cellulose triacetate (CTA), or the like. Thesecellulose esters are described in U.S. Pat. Nos. 1,698,049, 1,683,347,1,880,808, 1,880,560, 1,984,147, 2,129,052, and 3,617,201, and may beprepared using techniques known in the art or obtained commercially.Commercially available cellulose esters suitable herein include CA 320,CA 398, CAB 381, CAB 551, CAB 553, CAP 482, CAP 504, all available fromEastman Chemical Company, Kingsport, Tenn. Such cellulose esterstypically have a number average molecular weight of between about 10,000and about 75,000. Other suitable water-swellable polymers are known inthe art as described, for example, in U.S. Pat. No. 8,728,445,incorporated by reference herein.

The hydrogel composition may also include conventional additives such asfillers, preservatives, pH regulators, softeners, thickeners, pigments,dyes, refractive particles, stabilizers, toughening agents,detackifiers, pharmaceutical agents, and permeation enhancers. In thoseembodiments wherein adhesion is to be reduced or eliminated,conventional detackifying agents may also be used. These additives, andamounts thereof, are selected in such a way that they do notsignificantly interfere with the desired chemical and physicalproperties of the hydrogel composition.

Absorbent fillers may be advantageously incorporated to control thedegree of hydration when the adhesive is on the skin or other bodysurface. Such fillers can include microcrystalline cellulose, talc,lactose, kaolin, mannitol, colloidal silica, alumina, zinc oxide,titanium oxide, magnesium silicate, magnesium aluminum silicate,hydrophobic starch, calcium sulfate, calcium stearate, calciumphosphate, calcium phosphate dihydrate, woven and non-woven paper andcotton materials. Other suitable fillers are inert, i.e., substantiallynon-adsorbent, and include, for example, polyethylenes, polypropylenes,polyurethane polyether amide copolymers, polyesters and polyestercopolymers, nylon and rayon. A preferred filler is colloidal silica,e.g., Cab-O-Sil® (Cabot Corporation, Boston Mass.).

Preservatives include, by way of example, p-chloro-m-cresol, phenylethylalcohol, phenoxyethyl alcohol, chlorobutanol, 4-hydroxybenzoic acidmethylester, 4-hydroxybenzoic acid propylester, benzalkonium chloride,cetylpyridinium chloride, chlorohexidine diacetate or gluconate,ethanol, and propylene glycol.

Compounds useful as pH regulators include, but are not limited to,glycerol buffers, citrate buffers, borate buffers, phosphate buffers, orcitric acid-phosphate buffers may also be included so as to ensure thatthe pH of the hydrogel composition is compatible with that of anindividual's body surface.

Suitable softeners include citric acid esters, such as triethylcitrateor acetyl triethylcitrate, tartaric acid esters such as dibutyltartrate,glycerol esters such as glycerol diacetate and glycerol triacetate;phthalic acid esters, such as dibutyl phthalate and diethyl phthalate;and/or hydrophilic surfactants, preferably hydrophilic non-ionicsurfactants, such as, for example, partial fatty acid esters of sugars,polyethylene glycol fatty acid esters, polyethylene glycol fatty alcoholethers, and polyethylene glycol sorbitan-fatty acid esters.

Preferred thickeners herein are naturally occurring compounds orderivatives thereof, and include, by way of example: collagen;galactomannans; starches; starch derivatives and hydrolysates; cellulosederivatives such as methyl cellulose, hydroxypropylcellulose,hydroxyethyl cellulose, and hydroxypropyl methyl cellulose; colloidalsilicic acids; and sugars such as lactose, saccharose, fructose andglucose. Synthetic thickeners such as polyvinyl alcohol,vinylpyrrolidone-vinylacetate-copolymers, polyethylene glycols, andpolypropylene glycols may also be used.

In embodiments, the adhesive drug layer is a composition that phaseseparates when moist as described in U.S. Pat. No. 8,481,059, which isincorporated herein by reference.

The adhesive/drug layer comprises one or more drugs, active agents,and/or therapeutic agents. One or more active agents can be included inthe composition of the invention. Suitable active agents that may beincorporated into the adhesives of the invention, include the broadclasses of compounds normally delivered through body surfaces andmembranes such as, by way of illustration and not limitation: analepticagents; analgesic agents; antiarthritic agents; anticancer agents,including antineoplastic drugs; anticholinergics; anticonvulsants;antidepressants; antidiabetic agents; antidiarrheals; antihelminthics;antihistamines; antihyperlipidemic agents; antihypertensive agents;anti-infective agents such as antibiotics, antifungal agents, antiviralagents and bacteriostatic and bactericidal compounds; antiinflammatoryagents; antimigraine preparations; antinauseants; antiparkinsonismdrugs; antipruritics; antipsychotics; antipyretics; antispasmodics;antitubercular agents; antiulcer agents; anxiolytics; appetitesuppressants; attention deficit disorder and attention deficithyperactivity disorder drugs; cardiovascular preparations includingcalcium channel blockers, antianginal agents, central nervous systemagents, beta-blockers and antiarrhythmic agents; caustic agents; centralnervous system stimulants; cough and cold preparations, includingdecongestants; cytokines; diuretics; genetic materials; herbal remedies;hormonolytics; hypnotics; hypoglycemic agents; immunosuppressive agents;keratolytic agents; leukotriene inhibitors; mitotic inhibitors; musclerelaxants; narcotic antagonists; nicotine; nutritional agents, such asvitamins, essential amino acids and fatty acids; ophthalmic drugs suchas antiglaucoma agents; pain relieving agents such as anesthetic agents;parasympatholytics; peptide drugs; proteolytic enzymes;psychostimulants; respiratory drugs, including antiasthmatic agents;sedatives; steroids, including progestogens, estrogens, corticosteroids,androgens and anabolic agents; smoking cessation agents;sympathomimetics; tissue-healing enhancing agents; tranquilizers;vasodilators including general coronary, peripheral and cerebral;vessicants; and combinations thereof.

In some embodiments, the adhesive/drug layer comprises one or moredrugs, active agents, and/or therapeutic agents for the treatment ofAlzheimer's disease, dementia, and schizophrenia. In some embodiments,adhesive/drug layer comprises one or more drugs including, but notlimited to donepezil and/or memantine.

The adhesive/drug layer may further comprise one or more permeationenhancers.

With some active agents, it may be desirable to administer the agentalong with a suitable permeation enhancer in order to achieve atherapeutically effective flux through the skin or mucosa. Selection ofsuitable permeation enhancers will depend upon the agent beingdelivered, as well as the enhancer's compatibility with the othercomponents of the adhesive. Exemplary permeation enhancers include, byway of illustration and not limitation, sulfoxides such asdimethylsulfoxide and decylmethylsulfoxide; ethers such as diethyleneglycol monoethyl ether and diethylene glycol monomethyl ether;surfactants such as sodium laurate, sodium lauryl sulfate,cetyltrimethylammonium bromide, benzalkonium chloride, Poloxamer (231,182, 184), Tween (20, 40, 60, 80) and lecithin; the 1-substitutedazacycloheptan-2-ones, particularly 1-n-dodecylcyclazacycloheptan-2-one;alcohols such as ethanol, propanol, octanol, decanol, benzyl alcohol,and the like; fatty acids such as lauric acid, oleic acid and valericacid; fatty acid esters such as isopropyl myristate, isopropylpalmitate, methylpropionate, and ethyl oleate; polyols and estersthereof such as propylene glycol, ethylene glycol, glycerol, butanediol,polyethylene glycol, and polyethylene glycol monolaurate; amides andother nitrogenous compounds such as urea, dimethylacetamide,dimethylformamide, 2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine,diethanolamine and triethanolamine; terpenes; alkanones; and organicacids, particularly salicylic acid and salicylates, citric acid andsuccinic acid; and mixtures thereof.

The release of active agents “loaded” into the adhesive of the inventiontypically involves both absorption of water and desorption of the agentvia a swelling-controlled diffusion mechanism. Active agent-containingadhesives may be included in adhesive cushions, wound dressings,transdermal drug delivery devices and the like.

In embodiments, the transdermal delivery system includes an optionalrelease liner 16 that at least partially contacts the adhesive layer.The release liner is a removable covering that prevents loss of theactive agent from the adhesive layer during storage and/or protects thedevice against contamination. The release liner is typically adisposable layer that is removed prior to application of the device tothe treatment site. In some embodiments, the release liner preferablydoes not absorb components of the adhesive layer, including the activeagent. In some embodiments, the release liner preferably impermeable tocomponents of the adhesive layer (including the active agent) andprevents release of components of the adhesive layer through the releaseliner. By impermeable, it is meant that the release liner prevents allor substantially all of the components of the adhesive layer frompassing completely through the release liner. In some embodiments, therelease liner is easily removed or stripped from the adhesive/drug layerwithout removing a portion or a substantial portion of the adhesive druglayer. In some embodiments, the release liner is formed of one or moreof a film, non-woven fabric, woven fabric, laminate, and combinationsthereof. In some embodiments, the release liner is a silicone-coatedpolymer film or paper. In some non-limiting embodiments, the releaseliner is a silicone-coated polyethylene terephthalate (PET) film, apolyester film, a silicone-coated polyester film, a fluorocarbon film,or a fluorocarbon or fluorosilicone coated polymer film. In someembodiments, the material for the release liner is treated with one ormore of silicone, fluorocarbons, or fluorosilicones. In one embodiment,the release liner is a comprised of a fluorocarbon or fluorosiliconecoated PET film. In other embodiments, the release liner is comprised ofa polyester foil or other metalized laminate. In some embodiments, therelease liner may include features to increase ease of removal. In someembodiment, the release liner includes a slit or cut 74 as shown in FIG.9 to assist in removal of the liner from the device.

The activity of a transdermal delivery system is defined (and dependentupon) the release rate of the active agent from the system, the totalduration of release from the system, and the surface area of thedelivery system.

In some embodiments, the backing layer overlays or overhangs at leastone edge of at least one of the segmented patch layers. In someembodiments, the backing layer overhangs about 0.5-1.0 cm of at leastone edge of at least one of the segmented patch layers.

FIGS. 6A-6C show some embodiments of an exemplary transdermal patch,device or system, generally designated at 40, having internal segmentedlayers therein. In this embodiment, the device includes a backing layer42, one or more optional adhesive interfacing layers 44, a segmentedintermediate layer 46, and an optional release liner 52. In embodiments,the intermediate layer comprises an adhesive layer 50 comprising thedrug or therapeutic agent. In embodiments, the intermediate layercomprises the adhesive drug layer 50 and a backing layer 48. In someembodiments, one or more of the backing layer, interfacing layer(s), andintermediate layer(s) are laminated together to form the transdermalpatch. In some embodiments, one or more of the backing layer,interfacing layer(s), and intermediate layer(s) are at least partiallysegmented. In the embodiment as shown in FIG. 6C, the transdermaldelivery system 40 comprises a backing or overlay layer 42, an adhesiveinterfacing layer 44, a segmented intermediate layer 46, and a releaseliner 52. In this embodiment, the segmented intermediate layer comprisesa backing layer 48 that may be occlusive or breathable, an adhesive druglayer 50, a rate-controlling tie layer or membrane 58, and a contactadhesive layer 60.

The interfacing adhesive layer or layers adheres or connects the backinglayer to the segmented patch layers (at least the uppermost layer). Inembodiments, the interfacing layer is comprised of one or more polymersselected from acrylates, polyisobutylenes, silicone adhesives,polystyrene butyl rubber, polyethylene vinyl acetate and copolymersthereof. In some embodiments, the interfacing adhesive layers arecomprised of a cross-linked acrylate adhesive or its mixture. Exemplarycross-linked acrylate adhesives include the adhesives sold under thename Duro-Tak®. Specific, but not limiting, Duro-Tak® adhesives includeDuro-Tak® 387-2516, Duro-Tak® 387-2852, Duro-Tak® 87-2052 or mixturesthereof. In some embodiments, at least one interfacing adhesive layercomprises a polyisobutylene (PIB) or acrylate adhesive containingcrospovidone or colloidal silicone dioxide matrix modifiers. As shown inFIG. 6B, in some embodiments the interfacing layer comprises one or moreadhesive layers. In some embodiments, the interfacing layer comprises aplurality of adhesive layers. In some embodiments as shown in FIGS. 6Band 8 , the interfacing layer comprises at least a first adhesive layer54 and a second adhesive layer 56. In these embodiments, the firstadhesive layer is formed of a material having good adhesion to thebacking layer material. In embodiments, the first adhesive layer shouldnot bleed into the backing layer, especially where the backing layer isa fabric. The second adhesive layer is preferably formed of a materialhaving good adhesion to the proximal layer of the segmented patch. Insome embodiments, the second adhesive layer is formed of a materialhaving good adhesion to skin. It will be appreciated that theinterfacing layer is comprised of at least one or a plurality ofadhesive layers.

In some embodiments, the interfacing adhesive layer or at least onelayer of the interfacing layer overlays or overhangs at least one edgeof at least one of the segmented patch layers. In some embodiments, theadhesive layer or layers overhang about 0.5-1.0 cm of at least one edgeof at least one of the segmented patch layers. It will be appreciatedthat one or more or all of the backing layer, first adhesive layer andsecond adhesive layer may overlay or overhang at least one edge of thesegmented patch layers. It will further be appreciated that the backinglayer, first adhesive layer and/or the second adhesive layer may overlayor overhang the same or different amounts.

In some embodiments, one or more of the interfacing adhesive layers iscomprised of one or more pressure sensitive adhesive polymers. Inembodiments, the adhesive polymer is an acrylic polymer. In someembodiments, the adhesive polymer is an acrylic pressure sensitiveadhesive polymer. In embodiments, the acrylic polymer is an acrylate oracrylate copolymer, or polyacrylate adhesive polymer. An acrylicpressure sensitive adhesive polymer is a polyacrylate that is a polymerof copolymer of a monomer or monomers selected from acrylic acid estersand methacrylic acid esters. Other monomers, such as acrylic acid andvinyl acetate, may be present. In embodiments, the acrylic polymer isbased on acrylic esters such as 2-ethylhexyl acrylate (2-EHA) and ethylacrylate. In some embodiments, the polyacrylate polymer is a polymer ora copolymer of a monomer or monomers selected from acrylic acid andvinyl acetate. In embodiments, the acrylic polymer adhesive has pendentcarboxyl (—COOH) or hydroxyl (—OH) functional groups. In embodiments,the acrylic polymer adhesive comprises at least one of polyacrylate,polymethacrylate, derivatives thereof, and co-polymers thereof. Inembodiments, the acrylic adhesive is comprised of an acrylate copolymercomprising acrylic ester monomers or vinyl acetate monomers. Exemplaryacrylate copolymers are sold under the trade-name DU RO-TAK®.

In some embodiments, one or more of the interfacing adhesive layers iscomprised of one or more polymers comprising a pyrrolidone group,polyisobutylenes, polybutenes, mixtures and co-polymers thereof. In someembodiments, one or more of the interfacing adhesive layers is comprisedof a crosslinked polyvinylpyrrolidone. One exemplarypolyvinylpyrrolidone is a crospovidone such as the micronizedcrospovidone sold under the name Kollidon® CL-M available from BASF. Inembodiments, the adhesive matrix comprises a blend or mixture ofpolyisobutylene and polybutene polymers. Polyisobutylene is a vinylpolymer comprised of the isobutylene monomer. Polybutene is a viscous,non-drying, liquid polymer, prepared by copolymerization of 1- and2-butene with a small quantity of isobutylene. In some embodiments, thepolybutene in one embodiment has a molecular weight of between about750-6000 Daltons, preferably between about 900-4000 Daltons, andpreferably between about 900-3000 Daltons. In some embodiments themixture comprises polybutene in the polyisobutylene blend at about 40weight percent. More generally, the polybutene is present in thepolyisobutylene blend in an amount between 20-50 weight percent, orbetween 25-45 weight percent.

In some embodiments, one or more of the interfacing adhesive layers iscomprised of one or more silicone based adhesives, a medical adhesive, atissue adhesive, a surgical adhesive, or a combination of adhesives. Itwill be appreciated that the adhesives and features as described forabove embodiments may be used in the present embodiments.

In embodiments, the interfacing adhesive layers have a thickness ofabout 0.5-5 mil. In non-limiting embodiments, the interfacing adhesivelayers have a thickness of between about 0.5-0.75 mil, 0.5-1 mil,0.5-1.5 mil, 0.5-2 mil, 0.5-2.5 mil, 0.5-3 mil, 0.5-3.5 mil, 0.5-4 mil,0.5-4.5 mil, 0.75-1 mil, 0.75-1.5 mil, 0.75-2 mil, 0.75-2.5 mil, 0.75-3mil, 0.75-3.5 mil, 0.75-4 mil, 0.75-4.5 mil, 0.75-5 mil, 1-1.5 mil, 1-2mil, 1-2.5 mil, 1-3 mil, 1-3.5 mil, 1-4 mil, 1-4.5 mil, 1-5 mil, 1.5-2mil, 1.5-2.5 mil, 1.5-3 mil, 1.5-3.5 mil, 1.5-4 mil, 1.5-4.5 mil, 1.5-5mil, 2-2.5 mil, 2-3 mil, 2-3.5 mil, 2-4 mil, 2-4.5 mil, 2-5 mil, 2.5-3mil, 2.5-3.5 mil, 2.5-4 mil, 2.5-4.5 mil, 2.5-5 mil, 3-3.5 mil, 3-4 mil,3-4.5 mil, 3-5 mil, 3.5-4 mil, 3.5-4.5 mil, 3.5-5 mil, 4-4.5 mil, 4-5mil, or 4.5-5 mil. In some specific but non-limiting embodiments, theinterfacing adhesive layers have a thickness of about 0.5 mil, 1 mil,1.5 mil, 2 mil, 2.5 mil, 3 mil, 3.5 mil, 4 mil, 4.5 mil, or 5 mil.

An intermediate layer 46 is positioned between the interfacing adhesivelayer 44 and the optional release liner 52 or skin. In some embodiments,at least the intermediate layer is at least partially segmented,divided, or cut. In some embodiments, the intermediate layer issegmented, divided, cut, or otherwise separated into a plurality ofsectioned parts. FIG. 7 is an illustration of the segmented intermediatelayer 46 as viewed from above. The overhang of the backing layer 42and/or interfacing adhesive layer 44 is shown around the circumferenceof the intermediate layer. In this embodiment, the segments are made bycuts or divisions 64 in a cross-hatch pattern. In other words, thesegments are made by cuts or divisions along the length and width (inthis top-down view) of the intermediate layer. It will be appreciatedthat the segments may be formed by cuts or divisions along the length orwidth of the intermediate layer. In this embodiment, the patch segmentsor portions 62 will have an elongated strip shape. The cuts or divisionspreferably are made through the entirety of the intermediate layer.Thus, the intermediate layer is made up of a plurality of patch segmentsor portions 62. The cuts or divisions allow movement of the portionswithin the patch including movement in different directions.

As noted above, in some embodiments, the cuts or incisions do not extendacross the entirety of the layer such that the layer is not divided intoseparate segments. As shown in FIG. 9 , the cuts or incisions may notintersect and/or may not extend to an edge of the layer.

Each segment or portion may have size (from a top/bottom view) of about2-30 cm². In some embodiments, each segment or portion may have a sizeof about 2-25 cm², 2-20 cm², 2-15 cm², 2-10 cm², 2-5 cm², 5-30 cm², 5-25cm², 5-20 cm², 5-15 cm², 5-10 cm², 10-30 cm², 10-25 cm², 10-20 cm²,10-15 cm², 15-30 cm², 15-25 cm², 15-20 cm², 20-30 cm², 20-25 cm², orabout 25-30 cm². It will be appreciated that the segments may have thesame or different sizes. For example, the size of the segments near theouter edge of the patch may have a larger or smaller size than segmentspositioned near the center of the patch. The segments may have any shapeas suitable for forming the intermediate layer and providing movementwithin the patch. In some embodiments, the segments have a square,rectangular or other polygonal shape. It will be appreciated that thesegments may all have the same or different shapes within a singlelayer.

In embodiments, the intermediate layer comprises at least one or aplurality of layers. In embodiments, the intermediate layer comprises atleast an intermediate backing layer 48 and an adhesive drug layer 50comprising an active agent, therapeutic agent or drug. As seen in FIG.6A, the adhesive backing layer 48 is positioned between the interfacinglayer 44 or layers and the adhesive drug layer 50. It will beappreciated that one or more of the plurality of individual layers ofthe intermediate layer may include cuts, incisions or divisions at leastpartially through the respective layer.

The intermediate backing layer may be formed of materials as describedfor backing layers above. In some embodiments, the intermediate backinglayer is formed of an occlusive material. In some embodiments, theintermediate backing layer is formed of an occlusive polymer film orlaminate. In other embodiments, the intermediate backing layer is formedof a breathable material. In some non-limiting embodiments, theintermediate backing layer comprises a polymer film comprised of apolymer selected from at least one of polyesters, polyethylenes,polypropylenes, nylon, and/or polystyrenes. In some embodiments, thepolymer is selected from at least one of polyethylene terephthalate,ethylene vinyl acetate, polyethylene vinylacetate copolymer,polystyrene, and/or polyvinylchloride, and copolymers thereof. In oneembodiment the intermediate backing layer is comprised of a polyethyleneterephthalate/ethylene vinyl acetate laminate such as the Scotchpak™1012 (3M).

The intermediate layer further comprises one or more adhesive drug(active agent or therapeutic agent) layers 50 positioned between theintermediate backing layer and the release liner 52 where present. Inembodiments, the adhesive drug layer comprises one or more active agent,therapeutic agent or drug as described above. The adhesive/drug layer asdescribed above is useful for use in this embodiment.

In some embodiments, the intermediate layer comprises one or moreadditional layers. In some embodiments, the intermediate layer includesat least one tie layer 58. In some embodiments, the tie layer ispositioned between the adhesive drug layer and the release liner wherepresent. In some embodiments, the tie layer is an adhesive tie layer asdescribed above. In some embodiments, the tie layer is comprised of anonwoven fabric or a nonwoven, porous polymer membrane material. In someembodiments, the tie layer is a rate controlling membrane. In onenon-limiting embodiment, the tie layer is comprised of a microporouspolypropylene film. One exemplary film is the Celgard 2400 microporousfilm.

In some embodiments, the intermediate layer comprises one or morecontact adhesive layers 60 positioned between the adhesive drug layer ortie layer, where present, and the release liner, where present. Thecontact adhesive layer adheres the patch to the subject's skin. Thus,the contact adhesive layer may be formed of one or more adhesives usefulfor adhering a patch to skin as described above.

FIG. 8 is an exploded view of one embodiment of a transdermal patchcomprising a segmented intermediate layer. The patch in this embodimentcomprises, in order, a bi-elastic fabric backing layer 42, a firstinterfacing adhesive layer 54 formed of a first polymer film, a secondinterfacing adhesive layer 56, formed of a second polymer film that isdifferent than the first polymer film, a segmented intermediate layer46, and a protective release liner 52. The segmented intermediate layercomprises an occlusive backing layer 48, an adhesive drug layer 50, arate-controlling tie layer 58, and a contact adhesive layer 60.

In embodiments, the backing layer has a thickness of between about 0.5-3mil. In some embodiments, the backing layer has a thickness of about0.5-0.75 mil, 0.5-1 mil, 0.5-1.5 mil, 0.5-2 mil, 0.5-2.5 mil, 0.75-1mil, 0.75-1.5 mil, 0.75-2 mil, 0.75-2.5 mil, 0.75-3 mil, 1-1.5 mil, 1-2mil, 1-2.5 mil, 1-3 mil, 1.5-2 mil, 1.5-2.5 mil, 1.5-3 mil, 2-2.5 mil,2-3 mil, or 2.5-3 mil. In embodiments, the adhesive drug layer has athickness of between about 1 to 25 mil. In some embodiments, theadhesive drug layer has a thickness of between about 1-20 mil, 1-15 mil,1-10 mil, 1-5 mil, 5-25 mil, 5-20 mil, 5-15 mil, 5-10 mil, 10-25 mil,10-20 mil, 10-15 mil, 15-25 mil, or 15-20 mil. In some embodiments, therate-controlling tie layer has a thickness of between about 0.5 to 10mil. In some embodiments, the tie layer has at thickness of about 0.5-9mil, 0.5-8 mil, 0.5-7 mil, 0.5-6 mil, 0.5-5 mil, 0.5-4 mil, 0.5-3 mil,0.5-2 mil, 0.5-1.5 mil, 0.5-1 mil, 0.5-0.75 mil, 0.75-10 mil, 0.75-9mil, 0.75-8 mil, 0.75-7 mil, 0.75-6 mil, 0.75-5 mil, 0.75-4 mil, 0.75-3mil, 0.75-2 mil, 0.75-1.5 mil, 0.75-1 mil, 1-10 mil, 1-9 mil, 1-8 mil,1-7 mil, 1-6 mil, 1-5 mil, 1-4 mil, 1-3 mil, 1-2 mil, 1-1.5 mil, 1.5-10mil, 1.5-9 mil, 1.5-8 mil, 1.5-7 mil, 1.5-6 mil, 1.5-5 mil, 1.5-4 mil,1.5-3 mil, 1.5-2 mil, 2-10 mil, 2-9 mil, 2-8 mil, 2-7 mil, 2-6 mil, 2-5mil, 2-4 mil, 2-3 mil, 3-10 mil, 3-9 mil, 3-8 mil, 3-7 mil, 3-6 mil, 3-5mil, 3-4 mil, 4-10 mil, 4-9 mil, 4-8 mil, 4-7 mil, 4-6 mil, 4-5 mil,5-10 mil, 5-9 mil, 5-8 mil, 5-7 mil, 5-6 mil, 6-10 mil, 6-9 mil, 6-8mil, 6-7 mil, 7-10 mil, 7-9 mil, 7-8 mil, 8-10 mil, 8-9 mil, or 9-10mil. In some embodiments, the contact adhesive layer has a thickness ofabout 1 to 5 mil. In some embodiments, the contact adhesive layer has athickness of about 1-4 mil, 1-3 mil, 1-2 mil, 2-5 mil, 2-4 mil, 2-3 mil,3-5 mil, 3-4 mil, or 4-5 mil.

Examples 4-6 describe in vivo adhesion studies of patches including asegmented layer and having various formulations and configurations. Theresults of these studies are presented in Table 1.

TABLE 1 Adhesion Study Results Formulation Example 4 Example 5 Example 6# Test 18 9 9 14 7 7 7 subjects (total) (total) Breathable Control KOBPU KOB KOB KOB KOB KOB Top Layer Border 0 0 0 0 0.5 1 0 0.5 distance(cm) Mean 2.2 1.3 1.8 1.9 1.8 0.2 1.0 0.5 Adhesion Score

Example 4 considered the effect of a segmented intermediate layer on atransdermal patch as well as the effect of the backing layer compositionon patch adhesion. Both of the patches including a segmentedintermediate layer had a lower adhesion score indicating a greaterpercentage of the patch area adhered to the skin over the seven days ofwear. For both of the segmented patches, the adhesion score was <2 sothat ≥75% to <90% of the patch remained adhered to the skin over thetest period. In contrast, the patch without a segmented layer had a muchlower adhesion score where at least 25% (and up to half) of the patchlifted off the skin. Among the segmented patches, the patch comprising awoven bi-elastic polyester fabric (KOB 053 available from Karl Otto GmbH& Co.) as the backing layer had better adhesion than the patches havinga polyurethane film backing layer.

Example 5 considered the effect of having the backing layer overhang thesegmented intermediate layer. Transdermal patches were prepared with thesame composition and layers. A control patch had no overhang where theedge of the backing layer was flush with the edge of the intermediatelayer. The control was compared to patches having an overhang of 0.5 cmor 1.0 cm. As seen in Table 1, the patch having the 1.0 cm hadexceptional adhesion where nearly 90% of the patch area remained adheredto the skin. The control and 0.5 cm overhang patches both had goodadhesion with an adhesion score of less than 2 so that ≥75% to <90% ofthe patch remained adhered. The use of a border or overhang improvedadhesion as compared to the patch without a border.

Example 6 considered the effect of different compositions andconfigurations of the segmented intermediate layer on adhesion. Acontrol patch without overhang (where the edge of the backing layers wasflush with the edge of the intermediate layer) was compared to a patchhaving an overhang of a 0.5 cm border. As seen in Table 1, the patchhaving a 0.5 cm border had over 90% adhesion. Thus, an improvement inadhesion over the patch with an overhang may be achieved by adjustingthe formulation.

Thus, segmenting at least a portion of the transdermal patch provided anincrease in skin adhesion, especially over an extended wear duration.

The transdermal patch including a segmented portion may be prepared tohave a thickness such that the desired amount of drug formulation iscontained within the patch including the desired components whilemaintaining a thickness that is wearable and comfortable for the subjectas described above.

In some embodiments, the transdermal patch has a size or surface area ofabout 5-200 cm². In some non-limiting embodiments, the transdermal patchhas a size or surface area of about 5-10 cm², 5-15 cm², 5-20 cm², 5-25cm², 5-30 cm², 5-40 cm², 5-45 cm², 5-50 cm², 5-60 cm², 5-70 cm², 5-75cm², 5-80 cm², 5-90 cm², 5-100 cm², 5-125 cm², 5-150 cm², 5-175 cm²,10-15 cm², 10-20 cm², 10-25 cm², 10-30 cm², 10-40 cm², 10-45 cm², 10-50cm², 10-60 cm², 10-70 cm², 10-75 cm², 10-80 cm², 10-90 cm², 10-100 cm²,10-125 cm², 10-150 cm², 10-175 cm², 10-200 cm², 15-20 cm², 15-25 cm²,15-30 cm², 15-40 cm², 15-45 cm², 15-50 cm², 15-60 cm², 15-70 cm², 15-75cm², 15-80 cm², 15-90 cm², 15-100 cm², 15-125 cm², 15-150 cm², 15-175cm², 15-200 cm², 20-25 cm², 20-30 cm², 20-40 cm², 20-45 cm², 20-50 cm²,20-60 cm², 20-70 cm², 20-75 cm², 20-80 cm², 20-90 cm², 20-100 cm²,20-125 cm², 20-150 cm², 20-175 cm², 20-200 cm², 25-30 cm², 25-40 cm²,25-45 cm², 25-50 cm², 25-60 cm², 25-70 cm², 25-75 cm², 25-80 cm², 25-90cm², 25-100 cm², 25-125 cm², 25-150 cm², 25-175 cm², 25-200 cm², 30-40cm², 30-45 cm², 30-50 cm², 30-60 cm², 30-70 cm², 30-75 cm², 30-80 cm²,30-90 cm², 30-100 cm², 30-125 cm², 30-150 cm², 30-175 cm², 30-200 cm²,40-45 cm², 40-50 cm², 40-60 cm², 40-70 cm², 40-75 cm², 40-80 cm², 40-90cm², 40-100 cm², 40-125 cm², 40-150 cm², 40-175 cm², 40-200 cm², 45-50cm², 45-60 cm², 45-70 cm², 45-75 cm², 45-80 cm², 45-90 cm², 45-100 cm²,45-125 cm², 45-150 cm², 45-175 cm², 45-200 cm², 50-60 cm², 50-70 cm²,50-75 cm², 50-80 cm², 50-90 cm², 50-100 cm², 50-125 cm², 50-150 cm²,50-175 cm², 50-200 cm², 60-70 cm², 60-75 cm², 60-80 cm², 60-90 cm²,60-100 cm², 60-125 cm², 60-150 cm², 60-175 cm², 60-200 cm², 70-75 cm²,70-80 cm², 70-90 cm², 70-100 cm², 70-125 cm², 70-150 cm², 70-175 cm²,70-200 cm², 80-90 cm², 80-100 cm², 80-125 cm², 80-150 cm², 80-175 cm²,80-200 cm², 90-100 cm², 90-125 cm², 90-150 cm², 90-175 cm², 90-200 cm²,100-125 cm², 100-150 cm², 100-175 cm², 100-200 cm², 125-150 cm², 125-175cm², 125-200 cm², 150-175 cm², 150-200 cm², or 175-200 cm². In specific,but not limiting, embodiments, the transdermal patch has a size orsurface area of about 5 cm², 10 cm², 15 cm², 20 cm², 25 cm², 30 cm², 40cm², 45 cm², 50 cm², 60 cm², 70 cm², 75 cm², 80 cm², 90 cm², 100 cm²,125 cm², 150 cm², 175 cm², or 200 cm².

III. Methods of Treatment

Based on the exemplary compositions and devices described herein, andthe data showing release effective long term administration of thedevice, a method for prolonged or long term administration of an activeagent is provided herein.

The methods and systems described herein may be used for treating orpreventing any condition receptive to treatment with a therapeuticagent, drug or active agent as described herein. The methods and systemsdescribed herein are particularly useful for long term transdermaladministration of the therapeutic agent, drug or active agent. Inembodiments, the transdermal device is suitable for administration ofthe active agent or agents for at least about 3-14 days or more.

IV. Examples

The following examples are illustrative in nature and are in no wayintended to be limiting.

While a number of exemplary aspects and embodiments have been discussedabove, those of skill in the art will recognize certain modifications,permutations, additions and sub-combinations thereof. It is thereforeintended that the following appended claims and claims hereafterintroduced are interpreted to include all such modifications,permutations, additions and sub-combinations as are within their truespirit and scope.

All patents, patent applications, patent publications, and otherpublications mentioned herein are hereby incorporated by reference intheir entirety. Where a patent, application, or publication containsexpress definitions, those definitions should be understood to apply tothe incorporated patent, application or publication in which they arefound and not to the present application unless otherwise indicated.

Example 1 Manufacture of Transdermal Delivery System with CompositeBacking

A thin layer of a stretchable or flexible polymer (1-40 mil) islaminated onto an occlusive backing (e.g. Scotchpak® 1012, polyesterfilm laminate) with an adhesive such as polyisobutylene (PIB), acrylate,a silicone adhesive or other binding agent to form a laminate consistingof occlusive backing/adhesive/stretchable or flexible polymer.

An adhesive drug formulation is blended, coated on a release liner, anddried. The adhesive drug formulation is laminated on the stretchable orflexible polymer side of the backing laminate.

Example 2 Manufacture of Backing Laminate

A thin polyurethane film (0.5 to 1.0 mil) with a paper carrier (e.g. 3MCOTran™ 9701 Backing, 2 mil polyurethane film) is used as the top layer.An occlusive backing, (e.g. Scotchpak® 1012, polyester film laminate) islaminated on the polyurethane film with an adhesive such aspolyisobutylene (PIB), acrylate, a silicone adhesive or other bindingagent to make a quad laminate consisting of a papercarrier/polyurethane/adhesive/occlusive backing.

The occlusive backing layer is kiss-cut to divide it into multiple,discrete pieces as attached on the flexible elastic layer such as apolyurethane film.

The size of each discrete occlusive backing piece ranges from about 10cm2 to about 40 cm2 depending on requirements. Each of the discretebacking pieces are adhered or stuck together on the polyurethane film bythe adhesive. The laminate may be rolled in further converting process.

Example 3 Manufacture of Transdermal Delivery System

An adhesive drug formulation is blended, coated on a release liner, anddried. The adhesive drug formulation is laminated on a discretely,kiss-cut occlusive film side of the backing laminate as prepared inExample 2. The paper carrier is removed from the polyurethane side toleave the final formulation laminate. It is die-cut into a required sizewhich is a large patch containing multiple discrete pieces of occlusivefilm but all other layers are continuous. An exemplary patch is shown inFIG. 4B.

Example 4 In Vivo Adhesion Study of Transdermal Delivery SystemComprising Segmented Intermediate Layer

An in vivo adhesion study was performed to investigate the effect onpatch adhesion by including a segmented patch layer as well as differentpatch configurations and formulations.

A control patch was formed comprising a flexible, occlusive backingcomprised of a laminate of polyester and ethylene vinyl acetatecopolymers (Scotchpak® 1012 available from 3M), an adhesive layer, and arelease liner. The adhesive formulation consisted of 8.03 wt % fumedsilica (Aerosil® 200P), 11.69 wt % propylene glycol, and 80.28 wt %Duro-Tak® 387-2287 adhesive. The adhesive was coated on a release linerand dried. A nonwoven PET fabric tie layer (Remay 2250) was imbeddedbetween two adhesive layers. One of the release liners was replaced withthe backing layer for form the final control laminate. The control patchwas formed by cutting the final laminate to a suitable size rectangularpatch.

A first segmented test patch was formed comprising flexible, occlusivebacking comprised of a polyurethane film (3M 9832 Polyurethane film, 0.8mil), an interfacing adhesive layer (polyisobutylene), a segmentedintermediate layer, and a release liner. The occlusive backing layer waslaminated to the interfacing adhesive layer. The intermediate layer wasformed using the adhesive formulation as described above and cut intotwelve separate pieces. The separated adhesive layer was laminated withthe laminated backing/interfacing layer and a release liner. Thelaminate was cut to a suitable size rectangular patch.

A second segmented test patch was formed comprising a flexible,occlusive backing comprised of a woven polyethylene terephthalate (PET)KOB fabric (15 mil), a first interfacial adhesive layer (Duro-Tak®387-2516 adhesive with a coat weight, 3 mg/cm²), a second interfacialadhesive layer (a mixture of PIB adhesive with a coat weight of 5mg/cm²), a segmented intermediate layer, and a release liner.

The occlusive backing layer was laminated to the first and secondinterfacing adhesive layers. The intermediate layer was formed using theadhesive formulation as described above and cut into twelve separatepieces. The separated adhesive layer was laminated to the laminatedbacking/interfacing layers. The laminate was cut to a suitable sizerectangular patch. FIG. 3 illustrates a patch according to the secondsegmented test patch.

In Vivo Adhesion Study

A control patch and a first or second segmented test patch was appliedto intact, healthy skin on the back of each of 18 volunteers. Ninevolunteers wore the patches with woven PET fabric/PIB layer and theother nine volunteers wore the patches with polyurethane/Duro-Tak®387-2516/PIB layer.

Each patch was scored for the degree of adhesion to the skin every dayfor 7 days according to the following scale:

Score 0=≥90% (essentially no lift off the skin)

Score 1=≥75% to <90% (some edges only lifting off the skin)

Score 2=≥50% to <75% (less than half of the patch lifting off the skin)

Score 3=≥0% to <50% (more than half of the patch lifting off the skin)

Score 4=0 adhered—patch detached completely.

Each score was weighted by multiplying score by number of subjectshaving the score. All of the scores were added and averaged by dividingthe total score by the total number of test subjects in order tocalculate the daily average adhesion score over 7 days. The dailyindividual scores across the 7 days were averaged again to determine the7 day mean adhesion score.

The 7 day mean adhesion scores were 1.3 for the woven PET fabric fromKOB, 1.8 for 0.8 mil polyurethane film, and 2.2 for the control,respectively.

These results show the breathable top layer improved the adhesion withthe segmented patch design significantly. The woven PET fabric performedbetter than polyurethane film as the breathable top layer.

Example 5 In Vivo Adhesion Study of Transdermal Delivery SystemComprising Segmented Intermediate Layer

An in vivo adhesion study was performed to investigate the effect onpatch adhesion by including an overlaid border of the backing layer overa segmented patch layer.

A placebo adhesive formulation comprised layer comprised 15% Eudragit®EPO, 10 wt % triethyl citrate, 5 wt % SPAN 20, 10 wt % glycerin, 13 wt %Kollidon® CL-M, and 47 wt % of Duro-Tak® 387-2287 acrylate adhesive. Aplacebo adhesive layer was formed by laminating an occlusive backing(Scotchpak® 1012) with a layer of the placebo adhesive formulation (coatweight of 10 mg/cm² (2 mil)), a rate-controlling tie layer (Celgard®2400), and a contact adhesive layer (5 wt % SPAN 20 (sorbitanmonolaurate), 10 wt % triethyl citrate, 20 wt % Kollidon® CL-M and 65 wt% of Duro-Tak® 387-2287 (coat weight of 5 mg/cm²)) to form an adhesivelaminate.

A test patch was formed by placing an occlusive backing (Scotchpak®1012) on top of the adhesive formulation layer and placing a releaseliner (Loparex® 7300) on the bottom of the contact adhesive layer.

A breathable top layer consisting of a woven PET fabric (KOB 053bi-elastic fabric) was laminated to first and second interfacialadhesive layers. The first interfacial adhesive was Duro-Tak® 387-2516with a coat weight of 3 mg/cm². The second interfacial adhesive was amixture of PIB adhesive (80 wt %) and Kollidon® CL-M (20 wt %) with acoat weight of 5 mg/cm².

The test patches were cut into 12 pieces, which were integrated byplacing the breathable top layer laminate over the patch (over theocclusive backing layer).

A control patch was prepared by integrating the breathable PETfabric/interfacial adhesive laminate such that the edge of thebreathable top layer was flush with the integrated patch edge withoutextended border of the breathable laminate.

A first overlaid patch was formed by integrating the breathable PETfabric/interfacial adhesive laminate such that the edge of thebreathable top layer extended beyond the integrated patch edge by 0.5cm.

A second overlaid patch was formed by PET fabric/interfacial adhesivelaminate such that the edge of the breathable top layer extended beyondthe integrated patch edge by 1.0 cm.

Each of the control, first overlaid patch and second overlaid patch wereassembled to a rectangular patch.

In Vivo Adhesion Study

A control patch and a first or second overlaid test patch was applied tointact, healthy skin on the back of each of 14 volunteers. Sevenvolunteers wore a control and a first overlaid patch (0.5 cm) and theother seven volunteers wore a control patch and a second overlaid patch(1.0 cm) for seven days.

Each of control, first overlaid patch and second overlaid patch wereevaluated for their adhesion for 7 days in comparison to the controlwithout border. Each patch was scored for the degree of adhesion to theskin every day for 7 days according to the scale as in Example 4.

Each score was weighted by multiplying the score by number of subjectshaving the score, and all the scores were added up and averaged bydividing total score by total number of test subjects to calculate dailyaverage adhesion score every day over 7 days. The daily Individualscores across 7 days were averaged again to determine the 7 day meanadhesion score.

The 7 day mean adhesion scores were 0.2 for the patch with a 1.0 cmborder, 1.8 for the patch with the 0.5 cm border, and 1.9 for the patchwith no border, respectively. The border improved the adhesion of thepatches with the patches having the 1.0 cm border and the patches remainadhered for all seven subjects for 7 days.

Example 6 In Vivo Adhesion Study of Transdermal Delivery SystemComprising Segmented Intermediate Layer

An in vivo adhesion study was performed to investigate the effect ofadhesive layer patch design on patch adhesion.

A breathable top layer was prepared by laminating a 15 mil thickbi-elastic woven PET fabric (KOB 053 available from Karl Otto Braun GmbH& Co. KG), a first interfacial adhesive layer (Duro-Tak® 387-2516 (10 wt%) mixed with Duro-Tak® 387-2287 (90 wt %) with a coat weight of 3mg/cm²) and a second interfacial adhesive layer (a mixture of PIBadhesive (80 wt %) and Kollidon® CL-M (20 wt %) with a coat weight of 5mg/cm²).

A drug-in-adhesive layer (test formulation) comprised 2.59 wt % sodiumbicarbonate, 10 wt % triethyl citrate, 2 wt % SPAN 20, 3 wt % lauryllactate, 10 wt % glycerin, 15 wt % Kollidon® CL-M, and 57.41 wt % ofDuro-Tak® 387-2287 acrylate adhesive. The drug-in-adhesive layer (coatweight 10 mg/cm², 2 mil) was laminated with a rate controlling membrane(Celgard® 2400), and a contact adhesive layer (2 wt % SPAN 20 (sorbitanmonolaurate), 3 wt % lauryl lactate, 10 wt % triethyl citrate, 20 wt %Kollidon® CL-M and 65 wt % of Duro-Tak® 387-2287; coat weight of thecontact adhesive was 5 mg/cm²) to form an adhesive laminate. Anocclusive backing (Scotchpak® 1012), the adhesive laminate and a releaseliner (Loparex® 7300) were laminated to form an intermediate layer. Theocclusive backing and adhesive laminate layer were segmented into 12pieces, which were integrated by placing the breathable top layerlaminate over the patch (on the occlusive backing layer) to form thetest patch. Two patches were prepared using the intermediate layer. Forthe first, the breathable top layer was placed so that the edge of thetop layer was flush with the edge of the intermediate layer. For thesecond, the breathable top layer was placed so that the edge of the toplayer extended beyond the first intermediate layer by 0.5 cm.

The control and test patch were a rectangular patch.

In Vivo Adhesion Study

The two different rectangular segmented patches, 0 and 0.5 cm borders,were evaluated for their adhesion for 7 days. A 0 and 0.5 cm overlaidpatches were applied to intact, healthy skin on the back of each of 9volunteers. Each volunteer had two patches with the same formulation,but different border/overlay applied. Each volunteer wore a patch havingno overlay border (0 cm) and a second patch having an overhangingoverlay border (0.5 cm). The patches were each worn for seven days.

Patches were tested for 9 volunteers in the same way as Example 4. Eachvolunteer wore two patches, one without a border and the other with aborder, 0.5 cm. Each patch was scored for the degree of adhesion to theskin every day for 7 days in the same way as Example 4.

Each score was weighted by multiplying score by number of subjectshaving the score and all the scores were added up and averaged bydividing the total score by the total number of test subjects tocalculate daily adhesion score every day over the 7 days. The averageddaily scores across the 7 days were averaged to determine the meanadhesion score for the 7 days.

The 7 day mean adhesion score was 0.5 for the 0.5 cm border and 1.0 forthe control without border.

Example 7 Manufacture of Transdermal Delivery System with CompositeBacking

A thin layer of KOB 053 woven polyester fabric (Karl Otto GmbH & Co.) islaminated onto a Scotchpak™ 1012 (3M®) polyester film laminate withDuro-Tak 87-2052, an acrylate copolymer pressure sensitive adhesive(Henkel Corporation) to form a laminate consisting of wovenfabric/adhesive/polymer film.

An adhesive drug formulation is blended, coated on a release liner, anddried. The adhesive drug formulation is laminated on the polymer filmside of the backing laminate.

Embodiments

1. A transdermal patch, comprising:

a first backing layer comprised of an elastic material;

an interfacing adhesive layer;

a second backing layer comprised of a plurality of segments that are atleast partially separated;

an adhesive active agent layer comprising at least one active agent; and

a release liner.

2. The transdermal patch of embodiment 1, wherein the second backinglayer and the adhesive active agent layer together comprise a compositelayer where the composite layer is comprised of a plurality of segmentsthat are at least partially separated.

3. The transdermal patch of embodiment 1, wherein the plurality ofsegments are at least partially connected.

4. The transdermal patch of embodiment 2, wherein the plurality ofsegments are at least partially connected.

5. The transdermal patch of the combined or separate embodiments 1-4,wherein the first backing layer is comprised of an elastic polymer film,a multi-directional elastic woven fabric, a multi-directional elasticnonwoven fabric, a stretchable polymer film, a stretchable woven fabric,or a stretchable nonwoven fabric.6. The transdermal patch of the combined or separate embodiments 1-5,wherein the polymer fabric or polymer film is comprised of one or morepolymers selected from polyesters, polyethylenes, polypropylenes,polyvinylchloride, polyethylene vinyl acetate or copolymers thereof, andpolyurethanes.7. The transdermal patch of the combined or separate embodiments 1-6,wherein the first backing layer has a thickness of about 0.2-50 mil.8. The transdermal patch of the combined or separate embodiments 1-7,wherein the interfacing adhesive layer is comprised of one or morepolymers selected from selected from acrylates, acrylate copolymers,polyisobutylene, silicone, polystyrene butyl rubber, polyethylene vinylacetate and copolymers thereof, and plasticized polymers.9. The transdermal patch of the combined or separate embodiments 1-8,wherein the second backing layer is comprised of a material selectedfrom an occlusive material and a breathable material.10. The transdermal patch of the combined or separate embodiments 1-9,wherein the second backing layer is comprised of one or more polymersselected from polyesters, polyethylenes, polypropylenes, polystyrenes,polyvinylchloride, and a polyethylene terephthalate/ethylene vinylacetate laminate.11. The transdermal patch of the combined or separate embodiments 2 and3-10, wherein the composite layer further comprises a tie layerpositioned distal to the adhesive active agent layer.12. The transdermal patch of embodiment 9, wherein the tie layer is arate-controlling membrane that controls the rate of active agentrelease.13. The transdermal patch of the combined or separate embodiments 2 and3-12, wherein the composite layer further comprises a contact adhesivelayer positioned between the adhesive active agent layer and the releaseliner.14. The transdermal patch of the combined or separate embodiments 2 and3-13, where each segment of the composite layer has a size of about 2-40cm².15. The transdermal patch of the combined or separate embodiments 1-14,wherein the interfacing adhesive layer comprises a first adhesive layeradjacent the first backing layer and a second adhesive layer adjacentthe second backing layer.16. The transdermal patch of the combined or separate embodiments 2 and3-15, wherein at least the first backing layer and the release liner aresized to extend about 0.5-1.0 cm beyond the perimeter of the compositeadhesive layer.17. The transdermal patch of the combined or separate embodiments 1-16,wherein the release liner is comprised of a material selected from asilicone coated material, a fluorocarbon coated material, and afluorosilicone coated material.18. The transdermal patch of the combined or separate embodiments 1-17,wherein at least the first backing layer and the interfacing adhesivelayers are laminated.19. The transdermal patch of the combined or separate embodiments 2 and3-18, wherein the layers of the composite layer are laminated.20. The transdermal patch of the combined or separate embodiments 1-19,wherein the adhesive active agent layer is comprised of an adhesivematrix.21. A method of transdermally administering an active agent, comprising:

removing a release liner from the transdermal patch of the combined orseparate embodiments 1-20; and

adhering the transdermal patch to the skin of a patient for a period upto about 10 days to deliver the active agent to said patient.

22. A transdermal patch, comprising:

a first backing layer comprised of a flexible and breathable material;

an interfacing adhesive layer;

a second backing layer comprised of a plurality of segments that are atleast partially separated;

an adhesive active agent layer comprising at least one active agent; and

a release liner.

23. The transdermal patch of embodiment 22, wherein the second backinglayer and the adhesive active agent layer together comprise a compositelayer where the composite layer is comprised of a plurality of segmentsthat are at least partially separated.

24. The transdermal patch of the combined or separate embodiments 22-23,wherein the first backing layer is comprised of an elastic polymer film,a multi-directional elastic woven fabric, a multi-directional elasticnonwoven fabric, a stretchable polymer film, a stretchable woven fabric,or a stretchable nonwoven fabric.25. The transdermal patch of the combined or separate embodiments 22-24,wherein the polymer fabric or polymer film is comprised of one or morepolymers selected from polyesters, polyethylenes, polyurethanes, andnylon.26. The transdermal patch of the combined or separate embodiments 22-25,wherein the polyester is selected from a polyester elastomer andpolyester terephthalate.27. The transdermal patch of the combined or separate embodiments 22-26,wherein the polyethylene is a polyethylene vinyl acetate copolymer.28. The transdermal patch of the combined or separate embodiments 22-27,wherein the nonwoven or woven fabric is formed of one or more polymerfibers.29. The transdermal patch of the combined or separate embodiments 22-28,wherein the one or more polymer fibers are formed of a polymer fiberselected from a polyester, cotton, silk, polypropylene, nylon,polystyrene, polyvinylchloride, and polyurethanes.30. The transdermal patch of the combined or separate embodiments 22-29,wherein the first backing layer has a thickness of about 0.2-50 mil.31. The transdermal patch of the combined or separate embodiments 22-30,wherein the second backing layer is comprised of an occlusive material.32. The transdermal patch of the combined or separate embodiments 22-31,wherein the occlusive material is a polymer film or polymer laminate.33. The transdermal patch of the combined or separate embodiments 22-32,wherein the polymer film or polymer laminate is comprised of polyesters,polyethylenes, polypropylenes, polystyrenes, polyvinylchloride, ornylon.34. The transdermal patch of the combined or separate embodiments 22-33,wherein the polyethylene is a polyethylene vinyl acetate copolymer.35. The transdermal patch of the combined or separate embodiments 22-34,wherein the second backing layer is comprised of a breathable material.36. The transdermal patch of the combined or separate embodiments 22-35,wherein the composite layer further comprises a tie layer positioneddistal to the adhesive active agent layer.37. The transdermal patch of the combined or separate embodiments 22-36,wherein the composite layer further comprises a contact adhesive layerpositioned between the adhesive active agent layer and the releaseliner.38. The transdermal patch of the combined or separate embodiments 22-37,where each segment of the composite layer has a size of about 2-40 cm².39. The transdermal patch of the combined or separate embodiments 22-38,wherein the interfacing adhesive layer is comprised of one or moreadhesives selected from acrylates, polyisobutylene, silicone,polystyrene butyl rubber, polyethylene vinyl acetate and copolymersthereof, polyethylene terephthalate, and plasticized polymers.40. The transdermal patch of the combined or separate embodiments 22-39,wherein the interfacing adhesive layer comprises a first adhesive layeradjacent the first backing layer and a second adhesive layer adjacentthe second backing layer.41. The transdermal patch of claim the combined or separate embodiments22-40, wherein the first backing layer and/or the interfacing adhesivelayer, and the release liner are sized to extend beyond a perimeter ofthe composite adhesive layer.42. The transdermal patch of the combined or separate embodiments 22-40,wherein at least one of the first backing layer and the interfacingadhesive layer extends about 0.5-1.0 cm beyond the perimeter of thecomposite adhesive layer.43. The transdermal patch of the combined or separate embodiments 22-41,wherein the release liner is comprised of a material selected from asilicone coated material, a fluorocarbon coated material, and afluorosilicone coated material.44. The transdermal patch of the combined or separate embodiments 22-43,wherein the second backing layer is impermeable to the at least oneactive agent.45. The transdermal patch of the combined or separate embodiments 22-44,wherein at least the first backing layer and interfacing adhesive layersare laminated.46. The transdermal patch of the combined or separate embodiments 22-45,wherein the layers of the composite layer are laminated.47. The transdermal patch of the combined or separate embodiments 22-46,wherein the adhesive active agent layer is comprised of an adhesivematrix.48. The transdermal patch of the combined or separate embodiments 22-47,wherein the segments of the composite adhesive layer are at leastpartially square or rectangular.49. A method of transdermally administering an active agent, comprising:

removing a release liner from the transdermal patch of the combined orseparate embodiments 22-48; and

adhering the transdermal patch to the skin of a patient for a period upto about 10 days to deliver the active agent to said patient.

50. A composite backing layer for use in a transdermal patch,comprising:

a first layer comprised of a polymer fabric or a polymer film;

a second layer comprised of one or more polymers having at least one of(i) a tensile strength of less than about 10 MPa and (ii) an elongationof at least about 10-50%;

a third layer comprised of one or more stretchable polymers having astretchability of at least about 10%;

wherein the first and second layers are in contact and the second andthird layers are in contact.

51. The composite backing layer of embodiment 50, wherein the polymerfabric or polymer film is comprised of one or more polymers selectedfrom polyesters, polyethylenes, polypropylenes, polyvinylchloride,polyethylene vinyl acetate or copolymers thereof, and polyurethanes.52. The composite backing layer of the combined or separate embodiments50-51, wherein the first layer is selected from a woven, a non-wovenpolymer fabric, an occlusive polymer film, a polymer laminate, and apolymer/metal laminate.53. The composite backing layer of the combined or separate embodiments50-52, wherein the first layer has a thickness of about 0.5-20 mil.54. The composite backing layer of the combined or separate embodiments50-53, wherein the second layer is an adhesive layer.55. The composite backing layer of embodiment 54, wherein adhesive layeris an adhesive tie layer.56. The composite backing layer of the combined or separate embodiments50-55, wherein the one or more polymers of the second layer are selectedfrom acrylates, polyisobutylene, silicone, polystyrene butyl rubber,polyethylene vinyl acetate and copolymers thereof, and plasticizedpolymers.57. The composite backing of the combined or separate embodiments 50-56,wherein the one or more polymers of the second layer have a low shearstrength.58. The composite backing layer of the combined or separate embodiments50-57, wherein the second layer has a thickness of about 0.5-30 mil.59. The composite backing layer of the combined or separate embodiments50-58, wherein the third layer is a non-woven or woven fabric formed ofone or more polymer fibers.60. The composite backing layer of embodiment 59, wherein the one ormore polymer fibers are formed of a polymer fiber selected frompolyester, cotton, silk, polypropylene, nylon, polystyrene,polyvinylchloride, and polyurethanes.61. The composite backing layer of the combined or separate embodiments50-60, wherein the stretchable polymers have a stretchability of atleast about 10% in at least one direction.62. The composite backing layer of the combined or separate embodiments50-61, wherein the third layer has a thickness of about 0.5-5 mil.63. The composite backing layer of the combined or separate embodiments50-62, wherein the third layer is attached to an adhesive drug layercomprising one or more drugs.64. The composite backing layer of embodiment 63, wherein the backinglayer is impermeable to the one or more drugs.65. The composite backing layer of the combined or separate embodiments50-64, wherein the backing layer is occlusive.66. The composite backing layer of the combined or separate embodiments50-65, wherein the first layer, second layer, and third layer arelaminated.67. The composite backing layer of the combined or separate embodiments50-66, wherein the backing has a surface area of at least about 5-250cm².68. A transdermal patch for delivery of an active agent, comprising:

(a) a composite backing layer comprising:

-   -   a first layer comprised of a polymer fabric or a polymer film;    -   a second layer comprised of one or more polymers having at least        one of (i) a tensile strength of less than about 10 MPa and (ii)        an elongation of at least about 50%;    -   a third layer comprised of a material selected from one or more        stretchable polymers having a stretchability of at least about        10%, a woven fabric and a non-woven fabric;    -   wherein the first layer, second layer, and third layers are        arranged in contact as a composite;

(b) an adhesive drug layer comprising the active agent; and

(c) a release liner.

69. The transdermal patch of embodiment 68, wherein the first layerpolymer fabric or polymer film is comprised of one or more polymersselected from polyesters, polyethylenes, polypropylenes,polyvinylchloride, polyethylene vinyl acetate or copolymers thereof, andpolyurethanes.70. The transdermal patch of embodiment 68, wherein the first layer isselected from an occlusive polymer film, a polymer laminate, apolymer/metal laminate, a breathable polymer film, a woven polymerfabric and a non-woven polymer fabric.71. The transdermal patch of the combined or separate embodiments 68-70,wherein the first layer has a thickness of about 0.5-200 mil.72. The transdermal patch of the combined or separate embodiments 68-71,wherein the second layer is an adhesive layer.73. The transdermal patch of embodiment 72, wherein the adhesive layeris an adhesive tie layer.74. The transdermal patch of the combined or separate embodiments 68-73,wherein the one or more polymers of the second layer are selected fromacrylates, polyisobutylene, silicone, polystyrene butyl rubber,polyethylene vinyl acetate and copolymers thereof, and plasticizedpolymers.75. The transdermal patch of the combined or separate embodiments 68-74,wherein the one or more polymers of the second layer have a low shearstrength.76. The transdermal patch of the combined or separate embodiments 68-75,wherein the second layer has a thickness of about 0.5-30 mil.77. The transdermal patch of the combined or separate embodiments 68-76,wherein the third layer is a non-woven or woven fabric formed of one ormore polymer fibers.78. The transdermal patch of embodiment 77, wherein the one or morepolymer fibers are formed of a polymer fiber selected from polyester,cotton, silk, polypropylene, nylon, polystyrene, polyvinylchloride, andpolyurethanes.79. The transdermal patch of the combined or separate embodiments 68-78,wherein the stretchable polymers have a stretchability of at least about10% in at least one direction.80. The transdermal patch of the combined or separate embodiments 68-79,wherein the third layer has a thickness of about 1-40 mil.81. The transdermal patch of the combined or separate embodiments 68-80,wherein the backing layer is occlusive.82. The transdermal patch of the combined or separate embodiments 68-81,wherein the backing layer is impermeable to the active agent.83. The transdermal patch of the combined or separate embodiments 68-82,wherein the adhesive drug layer is comprised of an adhesive matrix.84. The transdermal patch of the combined or separate embodiments 68-83,wherein the release liner is a silicone coated material.85. The transdermal patch of embodiment 84, wherein the release liner isa silicone coated PET, fluorocarbon, or fluorocarbon coated PET.86. The transdermal patch of the combined or separate embodiments 68-85,wherein the patch has a surface area of at least about 5-200 cm².87. A transdermal patch for delivery of an active agent, comprising:

(a) a backing layer;

(b) an adhesive drug layer comprising the active agent;

(c) a tie layer embedded within the adhesive drug layer; and

(d) a release liner.

88. The patch of embodiment 87, wherein the tie layer is comprised of atleast one polymer, a woven polymer fiber fabric, and a non-woven polymerfiber fabric.

89. A composite backing layer for use in a transdermal patch,comprising:

a first elastic or flexible layer comprised of one or more polymershaving at least one of (i) a tensile strength of less than about 10 MPaor (ii) an elongation of at least about 50%;

a second adhesive layer; and

a third layer comprised of a plurality of separated pieces of anocclusive or substantially occlusive material.

90. The composite backing of embodiment 89, wherein the first layer isformed of a woven or non-woven polymer fabric or an elastic polymerfilm.

91. The composite backing of the combined or separate embodiments 89-90,wherein the elastic polymer film is selected from a polyurethane film, athermoplastic polyester elastomer film, and a polyethylene vinyl acetatefilm.

92. The composite backing of the combined or separate embodiments 89-91,wherein the first layer has a thickness of about 0.5-20 mil.

93. The composite backing of the combined or separate embodiments 89-92,wherein the second adhesive layer is comprised of one or more adhesives.

94. The composite backing of embodiment 93, wherein the adhesive isselected from an acrylic adhesive, a polyisobutylene adhesive, and asilicone adhesive.

95. The composite backing of the combined or separate embodiments 89-94,wherein the second adhesive layer has a thickness of about 0.5-5 mil.

96. The composite backing of the combined or separate embodiments 89-95,wherein the occlusive or substantially occlusive material is selectedfrom polyesters, polyethylenes, a polyethylene vinylacetate,polypropylenes, polystyrenes, polyvinylchloride or copolymers thereof,and nylon.97. The composite backing of embodiment 96, wherein the third layer is alaminate.98. The composite backing of the combined or separate embodiments 89-97,wherein the separated pieces are square or rectangular.99. The composite backing of the combined or separate embodiments 89-98,wherein the third layer has a thickness of about 1-5 mil.100. A method of transdermally administering an active agent,comprising:

removing a release liner from the transdermal patch or a patchcomprising a backing of the combined or separate embodiments 22-99; and

adhering the transdermal patch to the skin of a patient for a period upto about 10 days to deliver the active agent to said patient.

While a number of exemplary aspects and embodiments have been discussedabove, those of skill in the art will recognize certain modifications,permutations, additions and sub-combinations thereof. It is thereforeintended that the following appended claims and claims hereafterintroduced are interpreted to include all such modifications,permutations, additions and sub-combinations as are within their truespirit and scope.

All patents, patent applications, patent publications, and otherpublications mentioned herein are hereby incorporated by reference intheir entirety. Where a patent, application, or publication containsexpress definitions, those definitions should be understood to apply tothe incorporated patent, application or publication in which they arefound and not to the present application unless otherwise indicated.

It is claimed:
 1. A transdermal patch, comprising: (a) an outermostbacking layer; (b) an interfacing adhesive layer; (c) a segmentedintermediate layer comprised of: (i) an occlusive backing layer, (ii) anadhesive active agent layer; and (iii) a contact adhesive layer; whereinthe segmented intermediate layer is comprised of a plurality of segmentsthat are at least partially separated, and (d) a removable release linerin contact with the contact adhesive layer.
 2. The transdermal patch ofclaim 1, wherein the segmented intermediate layer further comprises atie layer positioned between the adhesive active agent layer and thecontact adhesive layer.
 3. The transdermal patch of claim 2, wherein thetie layer is a microporous membrane.
 4. The transdermal patch of claim3, wherein the microporous membrane is a polypropylene microporousmembrane.
 5. The transdermal patch of claim 1, wherein outermost backinglayer is comprised of an elastic polymer film, a polymer fabric, amulti-directional elastic woven fabric, a multi-directional elasticnonwoven fabric, a stretchable polymer film, a stretchable woven fabric,or a stretchable nonwoven fabric.
 6. The transdermal patch of claim 1,wherein the outermost backing layer is comprised of an elastic material.7. The transdermal patch of claim 1, wherein the outermost backing layeris comprised of one or more polymers selected from polyesters,polyethylenes, polypropylenes, polyvinylchloride, polyethylene vinylacetate or copolymers thereof, and polyurethanes.
 8. The transdermalpatch of claim 1, wherein the interfacing adhesive layer is comprised ofone or more polymers selected from acrylates, acrylate copolymers,polyisobutylene, silicone, polystyrene butyl rubber, polyethylene vinylacetate and copolymers thereof, and plasticized polymers.
 9. Thetransdermal patch of claim 1, wherein the occlusive backing layer is alaminate comprising a polyester layer.
 10. The transdermal patch ofclaim 1, wherein the occlusive backing layer is comprised a materialfabricated from one or more polymers selected from polyesters,polyethylenes, polypropylenes, polystyrenes, polyvinylchloride, and apolyethylene terephthalate/ethylene vinyl acetate laminate.
 11. Thetransdermal patch of claim 1, where each segment of the composite layerhas a size of about 2-40 cm².
 12. The transdermal patch of claim 1,wherein at least the outermost backing layer and the release liner aresized to extend about 0.5-1.0 cm beyond the perimeter of the compositelayer.
 13. The transdermal patch of claim 1, wherein the release lineris comprised of a material selected from a silicone coated material, afluorocarbon coated material, and a fluorosilicone coated material. 14.The transdermal patch of claim 1, wherein at least the outermost backinglayer and the interfacing adhesive layers are laminated.
 15. Thetransdermal patch of claim 1, wherein the occlusive backing layer andthe adhesive active agent layer are laminated.
 16. The transdermal patchof claim 1, wherein the adhesive active agent layer, the contactadhesive layer, or both are comprised of an acrylic adhesive.
 17. Atransdermal patch, comprising: (a) an outermost backing layer; (b) aninterfacing adhesive layer; (c) a segmented intermediate layerconsisting of these layers: (i) an occlusive backing layer, (ii) anadhesive active agent layer; (iii) a microporous membrane; and (iv) acontact adhesive layer; wherein the segmented intermediate layer iscomprised of a plurality of segments that are at least partiallyseparated, and (d) a removable release liner in contact with the contactadhesive layer.
 18. A method for transdermally administering an activeagent, comprising: (i) removing a release liner from the transdermalpatch of claim 17; and (ii) adhering the transdermal patch to the skinof a patient for a period up to about 10 days to deliver the activeagent to said patient.